LE CHI (US)
WO2006116184A2 | 2006-11-02 | |||
WO2001062726A2 | 2001-08-30 |
US3215706A | 1965-11-02 |
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We claim: 1. A compound of formula (I) or formula (II): or or a pharmaceutically acceptable salt thereof, wherein, as permitted by valence and stability: X5 is =N–, –C(O)–, or =C(R4)–; R4 is hydroxyl; methoxy; amino; halogen; hydrogen; -N(R6)C(O)R5; or C1-6 alkyl, optionally substituted with one or more halogen; X1 is =N–, –N(OH)–, or –C(R7)=; X2 is –N=, –C(O)–, or –C(R11)=; X3 is –N= or –C(R8)=; X4 is =N– or =C(R12)– ; provided that no more than two of X1 to X5 are =N-; and when X1 is –N(OH)–, one and only one of X2 and X5 is –C(O)–; X6 is =N-, -NR13-, or =C(R7)-; X7 is =N-, -NR13-, or =C(R11)-; X8 is =N-, -NR13-, or =C(R8)-; X10 is =N-, -NR13-, or =C(R4)-; provided that, if at least three of X6 to X10 are =N-, one of X6 to X10 is -NR13-; R6 is H or C1-6 alkyl; R5 is C1-6 alkyl; R11 is hydrogen, halogen, C1-6 alkyl, amino, or –N(R6)C(O)R5; R12 is hydrogen, halogen, C1-6 alkyl, amino, or –N(R6)C(O)R5; R7 is hydrogen, hydroxyl, amino, halogen, or –N(R6)C(O)R5; R8 is hydrogen, hydroxyl, amino, halogen, or –N(R6)C(O)R5; or R4 and R7, or R4 and R8, or R7 and R11, or R8 and R12, together with the carbon atoms to which they are attached, combine to form a 5- to 6-membered carbocyclic or heterocyclic ring; R13 is hydrogen, halogen, C1-6 alkyl, amino, or –N(R6)C(O)R5; R1 is hydrogen or C1-6 alkyl; R2 is hydrogen or C1-6 alkyl; R3 is –ONR142, –NHNH2 or ; R14 is, independently at each occurrence, H or C1-6 alkyl; R9 is hydrogen or is C2-6 alkynyl, C2-6 alkenyl, C1-6 alkyl, each optionally substituted with one or more halogen, hydroxyl, amino, cyano, or alkoxy; and R10 is amino, –NHBoc, –ONH2, or –NHNH2; or R2 and R3, together with the carbon atom to which they are attached, combine to form . 2. The compound of claim 1, wherein R14 is, independently at each occurrence, H or CH3. 3. The compound of claim 1, wherein R3 is . 4. The compound of claim 1, wherein: R4 is hydroxyl; amino; halogen; hydrogen; -N(R6)C(O)R5; or C1-6 alkyl, optionally substituted with one or more halogen; R1 is hydrogen or C1-6 alkyl; R2 is hydrogen or C1-6 alkyl; R3 is –NHNH2 or ; and R10 is amino,–ONH2, or –NHNH2. 5. The compound of any one of claims 1-4 provided the compound is not , or . 6. The compound of claim 5, further provided that the compound is not . 7. The compound of any one of the preceding claims, wherein R3 is . 8. The compound of any one of the preceding claims, wherein X1 is CR7, X2 is CR11, X3 is CR8, X4 is CR12, and X5 is CR4; or X6 is CR7, X7 is CR11, X8 is CR8, and X10 is CR4. 9. The compound of claim 8, wherein R7 is H and R8 is H. 10. The compound of any one of the preceding claims, wherein X5 is CR4 and R4 is hydroxyl; or X10 is CR4 and R4 is hydroxyl. 11. The compound of any one of the preceding claims, wherein R1 is H and R2 is H. 12. The compound of any one of the preceding claims, wherein R7 is hydroxyl, halogen, or amino. 13. The compound of any one of the preceding claims, wherein the compound is: , or , or a pharmaceutically acceptable salt thereof. 14. The compound of any one of the preceding claims, wherein the compound is: , or . 15. The compound of any one of the preceding claims, wherein the compound is: 16. A method of treating Parkinson’s Disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or formula (II): or or a pharmaceutically acceptable salt thereof, wherein, as permitted by valence and stability: X5 is =N–, –C(O)–, or =C(R4)-; R4 is hydroxyl; methoxy; amino; halogen; hydrogen; -N(R6)C(O)R5; or C1-6 alkyl, optionally substituted with one or more halogen; X1 is =N–, –N(OH)–, or –C(R7)=; X2 is –N=, –C(O)–, or =C(R11)-; X3 is =N- or =C(R8)-; X4 is =N- or =C(R12)-; provided that no more than two of X1 to X5 are =N-; and when X1 is –N(OH)–, one and only one of X2 and X5 is –C(O)–; X6 is =N-, -NR13-, or =C(R7)-; X7 is =N-, -NR13-, or =C(R11)-; X8 is =N-, -NR13-, or =C(R8)-; X10 is =N-, -NR13-, or =C(R4)-; provided that, if at least three of X6 to X10 are =N-, one of X6 to X10 is -NR13-; R6 is H or C1-6 alkyl; R5 is C1-6 alkyl; R11 is hydrogen, halogen, C1-6 alkyl, amino, or –N(R6)C(O)R5; R12 is hydrogen, halogen, C1-6 alkyl, amino, or –N(R6)C(O)R5; R7 is hydrogen, hydroxyl, amino, halogen, or –N(R6)C(O)R5; R8 is hydrogen, hydroxyl, amino, halogen, or –N(R6)C(O)R5; or R4 and R7, or R4 and R8, or R7 and R11, or R8 and R12, together with the carbon atoms to which they are attached, combine to form a 5- to 6-membered carbocyclic or heterocyclic ring; R13 is hydrogen, halogen, C1-6 alkyl, amino, or –N(R6)C(O)R5; R1 is hydrogen or C1-6 alkyl; R2 is hydrogen or C1-6 alkyl; R3 is –ONR142, –NHNH2, or ; R14 is, independently at each occurrence, H or C1-6 alkyl; R9 is hydrogen or is C2-6 alkynyl, C2-6 alkenyl, C1-6 alkyl, each optionally substituted with one or more halogen, hydroxyl, amino, cyano, or alkoxy; and R10 is amino, –NHBoc, –ONH2, or –NHNH2; or R2 and R3, together with the carbon atom to which they are attached, combine to form . 17. The method of claim 16, wherein R14 is, independently at each occurrence, H or CH3. 18. The method of claim 16, wherein R3 is . 19. The method of claim 16, wherein: R4 is hydroxyl; amino; halogen; hydrogen; -N(R6)C(O)R5; or C1-6 alkyl, optionally substituted with one or more halogen; R1 is hydrogen or C1-6 alkyl; R2 is hydrogen or C1-6 alkyl; R3 is –NHNH2, -ONH2, or ; and R10 is amino, -ONH2, or –NHNH2. 20. The method of any one of claims 16-19, provided the compound is not , or . 21. The method of claim 20, further provided that the compound is not . 22. The method of any one of claims 16-19, wherein the compound of formula (I) is: , or . . 23. The method of claim 22, wherein the compound of formula (I) is , , , , , , or , or a pharmaceutically acceptable salt thereof. 24. A method of inhibiting a tyrosine decarboxylase (TyrDC) comprising contacting the TyrDC with a compound of formula (I) or formula (II): or or a pharmaceutically acceptable salt thereof, wherein: X5 is =N–, –C(O)–, or =C(R4)-; R4 is hydroxyl; methoxy; amino; halogen; hydrogen; -N(R6)C(O)R5; or C1-6 alkyl, optionally substituted with one or more halogen; X1 is =N–, –N(OH)–, or –C(R7)=; X2 is –N=, –C(O)–, or =C(R11)-; X3 is =N- or =C(R8)-; X4 is =N- or =C(R12)-; provided that no more than two of X1 to X5 are =N-; and when X1 is –N(OH)–, one and only one of X2 and X5 is –C(O)–; X6 is =N-, -NR13-, or =C(R7)-; X7 is =N-, -NR13-, or =C(R11)-; X8 is =N-, -NR13-, or =C(R8)-; X10 is =N-, -NR13-, or =C(R4)-; provided that, if at least three of X6 to X10 are =N-, one of X6 to X10 is -NR13-; R6 is H or C1-6 alkyl; R5 is C1-6 alkyl; R11 is hydrogen, halogen, C1-6 alkyl, amino, or –N(R6)C(O)R5; R12 is hydrogen, halogen, C1-6 alkyl, amino, or –N(R6)C(O)R5; R7 is hydrogen, hydroxyl, amino, halogen, or –N(R6)C(O)R5; R8 is hydrogen, hydroxyl, amino, halogen, or –N(R6)C(O)R5; or R4 and R7, or R4 and R8, or R7 and R11, or R8 and R12, together with the carbon atoms to which they are attached, combine to form a 5- to 6-membered carbocyclic or heterocyclic ring; R13 is hydrogen, halogen, C1-6 alkyl, amino, or –N(R6)C(O)R5; R1 is hydrogen or C1-6 alkyl; R2 is hydrogen or C1-6 alkyl; R3 is –ONR142, –NHNH2, or ; R14 is, independently at each occurrence, H or C1-6 alkyl; R9 is hydrogen or is C2-6 alkynyl, C2-6 alkenyl, C1-6 alkyl, each optionally substituted with one or more halogen, hydroxyl, amino, cyano, or alkoxy; and R10 is amino, –NHBoc, –ONH2, or –NHNH2; or R2 and R3, together with the carbon atom to which they are attached, combine to form . 25. The method of claim 24, wherein R14 is, independently at each occurrence, H or CH3. 26. The method of claim 24, wherein R3 is . 27. The method of claim 24, wherein: R4 is hydroxyl; amino; halogen; hydrogen; -N(R6)C(O)R5; or C1-6 alkyl, optionally substituted with one or more halogen; R1 is hydrogen or C1-6 alkyl; R2 is hydrogen or C1-6 alkyl; R3 is –NHNH2, -ONH2, or ; and R10 is amino, -ONH2, or –NHNH2. 28. The method of any one of claims 24-27, provided the compound is not , or . 29. The method of claim 28, further provided that the compound is not . 30. The method of any one of claims 24-27, wherein the compound of formula (I) is: , or . 31. The method of claim 30, wherein the compound of formula (I) is , , or a pharmaceutically acceptable salt thereof. 32. The method of any one of claims 24-31, wherein the TyrDC is Enterococcus faecalis TyrDC. 33. A compound of formula (Ia): or a pharmaceutically acceptable salt thereof, wherein: X5 is N or CR4; R4 is hydroxyl; methoxy; amino; halogen; hydrogen; -N(R6)C(O)R5; or C1-6 alkyl, optionally substituted with one or more halogen; X1 is N or CR7; X2 is N or CR11; X3 is N or CR8; X4 is N or CR12; provided that no more than two of X1 to X5 are N; R6 is H or C1-6 alkyl; R5 is C1-6 alkyl; R11 is hydrogen, halogen, or C1-6 alkyl; R12 is hydrogen, halogen, or C1-6 alkyl; R7 is hydrogen, hydroxyl, amino, or halogen; R8 is hydrogen, hydroxyl, amino, or halogen; or R4 and R7, or R4 and R8, together with the carbon atoms to which they are attached, combine to form a 5- to 6-membered carbocyclic or heterocyclic ring; R1 is hydrogen or C1-6 alkyl; R2 is hydrogen or C1-6 alkyl; R3 is –ONR142, –NHNH2, or ; R14 is, independently at each occurrence, H or C1-6 alkyl; R9 is hydrogen or is C2-6 alkynyl, C2-6 alkenyl, C1-6 alkyl, each optionally substituted with one or more halogen, hydroxyl, amino, cyano, or alkoxy; and R10 is amino, –NHBoc, –ONH2, or –NHNH2; or R2 and R3, together with the carbon atom to which they are attached, combine to form . 34. The compound of claim 33, wherein R14 is, independently at each occurrence, H or CH3. 35. The compound of claim 33, wherein R3 is . 36. The compound of claim 33, wherein: R4 is hydroxyl; amino; halogen; hydrogen; -N(R6)C(O)R5; or C1-6 alkyl, optionally substituted with one or more halogen; R1 is hydrogen or C1-6 alkyl; R2 is hydrogen or C1-6 alkyl; R3 is –NHNH2 or ; and R10 is amino,–ONH2, or –NHNH2. 37. The compound of any one of claims 33-36, provided the compound is not , or . 38. The compound of claim 37, further provided that the compound is not . 39. The compound of any one of claims 33-38, wherein R3 is . 40. The compound of any one of claims 33-39, wherein X1 is CR7, X2 is CR11, X3 is CR8, X4 is CR12, and X5 is CR4. 41. The compound of claim 40, wherein R7 is H and R8 is H. 42. The compound of any one of claims 33-41, wherein X5 is CR4 and R4 is hydroxyl. 43. The compound of any one of claims 33-42, wherein R1 is H and R2 is H. 44. The compound of any one of claims 33-43, wherein R7 is hydroxyl, halogen, or amino. 45. The compound of any one of claims 33-44, wherein the compound is: , , or . 46. The compound of any one of claims 33-45, wherein the compound is: , or . 47. The compound of claim 45, wherein the compound is: , , or . 48. A method of treating Parkinson’s Disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (Ia): or a pharmaceutically acceptable salt thereof, wherein: X5 is N or CR4; R4 is hydroxyl; methoxy; amino; halogen; hydrogen; -N(R6)C(O)R5; or C1-6 alkyl, optionally substituted with one or more halogen; X1 is N or CR7; X2 is N or CR11; X3 is N or CR8; X4 is N or CR12; provided that no more than two of X1 to X5 are N; R6 is H or C1-6 alkyl; R5 is C1-6 alkyl; R11 is hydrogen, halogen, or C1-6 alkyl; R12 is hydrogen, halogen, or C1-6 alkyl; R7 is hydrogen, hydroxyl, amino, or halogen; R8 is hydrogen, hydroxyl, amino, or halogen; or R4 and R7, or R4 and R8, together with the carbon atoms to which they are attached, combine to form a 5- to 6-membered carbocyclic or heterocyclic ring; R1 is hydrogen or C1-6 alkyl; R2 is hydrogen or C1-6 alkyl; R3 is –ONR142, –NHNH2, or ; R14 is, independently at each occurrence, H or C1-6 alkyl; R9 is hydrogen or is C2-6 alkynyl, C2-6 alkenyl, C1-6 alkyl, each optionally substituted with one or more halogen, hydroxyl, amino, cyano, or alkoxy; and R10 is amino, –NHBoc, –ONH2, or –NHNH2; or R2 and R3, together with the carbon atom to which they are attached, combine to form . 49. The method of claim 48, wherein R14 is, independently at each occurrence, H or CH3. 50. The method of claim 48, wherein R3 is . 51. The method of claim 48, wherein: R4 is hydroxyl; amino; halogen; hydrogen; -N(R6)C(O)R5; or C1-6 alkyl, optionally substituted with one or more halogen; R1 is hydrogen or C1-6 alkyl; R2 is hydrogen or C1-6 alkyl; R3 is–NHNH2, -ONH2, or ; R10 is amino, -ONH2, or -NHNH2. 52. The method of any one of claims 48-51, provided the compound is not , or . 53. The method of claim 52, further provided that the compound is not . 54. The method of claim 52 or claim 53, wherein the compound of formula (Ia) is: , , or . 55. The method of claim 54, wherein the compound of formula (I) is , , or , or a pharmaceutically acceptable salt thereof. 56. A method of inhibiting a tyrosine decarboxylase (TyrDC) comprising contacting the TyrDC with a compound of formula (Ia): or a pharmaceutically acceptable salt thereof, wherein: X5 is N or CR4; R4 is hydroxyl; methoxy; amino; halogen; hydrogen; -N(R6)C(O)R5; or C1-6 alkyl, optionally substituted with one or more halogen; X1 is N or CR7; X2 is N or CR11; X3 is N or CR8; X4 is N or CR12; provided that no more than two of X1 to X5 are N; R6 is H or C1-6 alkyl; R5 is C1-6 alkyl; R11 is hydrogen, halogen, or C1-6 alkyl; R12 is hydrogen, halogen, or C1-6 alkyl; R7 is hydrogen, hydroxyl, amino, or halogen; R8 is hydrogen, hydroxyl, amino, or halogen; or R4 and R7, or R4 and R8, together with the carbon atoms to which they are attached, combine to form a 5- to 6-membered carbocyclic or heterocyclic ring; R1 is hydrogen or C1-6 alkyl; R2 is hydrogen or C1-6 alkyl; R3 is -ONR142, –NHNH2, or ; R14 is, independently at each occurrence, H or C1-6 alkyl; R9 is hydrogen or is C2-6 alkynyl, C2-6 alkenyl, C1-6 alkyl, each optionally substituted with one or more halogen, hydroxyl, amino, cyano, or alkoxy; and R10 is amino, -NHBoc, –ONH2, or –NHNH2; or R2 and R3, together with the carbon atom to which they are attached, combine to form . 57. The method of claim 56, wherein R14 is, independently at each occurrence, H or CH3. 58. The method of claim 56, wherein R3 is . 59. The method of claim 56, wherein: R4 is hydroxyl; amino; halogen; hydrogen; -N(R6)C(O)R5; or C1-6 alkyl, optionally substituted with one or more halogen; R1 is hydrogen or C1-6 alkyl; R2 is hydrogen or C1-6 alkyl; R3 is –NHNH2, -ONH2, or ; R10 is amino, -ONH2, or –NHNH2. 60. The method of any one of claims 56-59, provided the compound is not , or . 61. The method of claim 60, further provided that the compound is not . 62. The method of any one of claims 56-60, wherein the compound is , , , , , , or . 63. The method of claim 62, wherein the compound of formula (I) is , , or , or a pharmaceutically acceptable salt thereof. 64. The method of any one of claims 56-63, wherein the TyrDC is Enterococcus faecalis TyrDC. |
, , or , or a pharmaceutically acceptable salt thereof. In some such embodiments, the compound is , or . In other such embodiments, the compound is: , or , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (I). In some embodiments, -N(R 6 )C(O)R 5 is –NHBoc. In some embodiments, R 4 is halogen, such as F or Cl. In other embodiments, R 4 is C 1-6 alkyl, optionally substituted with one or more halogen, such as CH 3 , CF 3 , CF 2 H, or CFH 2 . Also provided herein is a compound of formula (Ia): or a pharmaceutically acceptable salt thereof, wherein: X 5 is N or CR 4 ; R 4 is hydroxyl; methoxy; amino; halogen; hydrogen; -N(R 6 )C(O)R 5 ; or C 1-6 alkyl, optionally substituted with one or more halogen; X 1 is N or CR 7 ; X 2 is N or CR 11 ; X 3 is N or CR 8 ; X 4 is N or CR 12 ; provided that no more than two of X 1 to X 5 are N; R 6 is H or C 1-6 alkyl; R 5 is C 1-6 alkyl; R 11 is hydrogen, halogen, or C 1-6 alkyl; R 12 is hydrogen, halogen, or C 1-6 alkyl; R 7 is hydrogen, hydroxyl, amino, or halogen; R 8 is hydrogen, hydroxyl, amino, or halogen; or R 4 and R 7 , or R 4 and R 8 , together with the carbon atoms to which they are attached, combine to form a 5- to 6-membered carbocyclic or heterocyclic ring; R 1 is hydrogen or C 1-6 alkyl; R 2 is hydrogen or C 1-6 alkyl; R 3 is –ONR 14 2 , –NHNH 2 , or ; R 14 is, independently at each occurrence, H or C 1-6 alkyl; R 9 is hydrogen or is C 2-6 alkynyl, C 2-6 alkenyl, C 1-6 alkyl, each optionally substituted with one or more halogen, hydroxyl, amino, cyano, or alkoxy; and R 10 is amino, –NHBoc, –ONH 2 , or –NHNH 2 ; or R 2 and R 3 , together with the carbon atom to which they are attached, combine to form . In some embodiments, R 14 is, independently at each occurrence, H or CH 3 . In some embodiments, R 3 is . In some embodiments, R 4 is hydroxyl; amino; halogen; hydrogen; -N(R 6 )C(O)R 5 ; or C 1-6 alkyl, optionally substituted with one or more halogen; R 1 is hydrogen or C 1-6 alkyl; R 2 is hydrogen or C 1-6 alkyl; R 3 is –NHNH 2 or ; and R 10 is amino,–ONH 2 , or –NHNH 2 . In some embodiments, the compound is not , , or . In some such embodiments, the compound is not . In some embodiments, R 3 is . In some embodiments, X 1 is CR 7 , X 2 is CR 11 , X 3 is CR 8 , X 4 is CR 12 , and X 5 is CR 4 . In some such embodiments, R 7 is H and R 8 is H. In other such embodiments, R 7 is hydroxyl or halogen. In still other such embodiments, R 11 is halogen, such as fluorine or chlorine. In some embodiments, X 5 is CR 4 and R 4 is hydroxyl. In certain such embodiments, X 3 is –N=. In some embodiments, R 1 is H and R 2 is H. In some embodiments, R 7 is hydroxyl, halogen, or amino, such as hydroxyl or halogen. In some embodiments, X 1 is =N–. In some embodiments, X 2 is –N=. In some embodiments, X 3 is –N=. In some embodiments, X 4 is =N–. In some embodiments, R 9 is CFH 2 , CF 2 H, or CH 3 . In some such embodiments, R 10 is –NHNH 2 . In certain preferred such embodiments, R 9 is CFH 2 or CF 2 H. In some embodiments, the compound is: ,
, , or , or a pharmaceutically acceptable salt thereof. In some such embodiments, the compound is: , or . In other such embodiments, the compound is: : , , or , or a pharmaceutically acceptable salt thereof. Provided herein are compounds selected from:
, and , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is , , or , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is , , , or , or a pharmaceutically acceptable salt thereof. In some such embodiments, the compound is , , or , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is , , , or , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is , O , or , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is , , and , or a pharmaceutically acceptable salt thereof. In some such embodiments, the compound is not , or a pharmaceutically acceptable salt thereof. In other such embodiments, the compound is , , , or , or a pharmaceutically acceptable salt thereof. Pharmaceutical Compositions One or more compounds of this invention can be administered to a human patient by themselves or in pharmaceutical compositions where they are mixed with biologically suitable carriers or excipient(s) at doses to treat or ameliorate a disease or condition as described herein. Mixtures of these compounds can also be administered to the patient as a simple mixture or in suitable formulated pharmaceutical compositions. For example, some aspects of the invention relates to a pharmaceutical composition comprising a compound disclosed herein (e.g., a therapeutically effective dose of a compound disclosed herein), or a pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, enantiomer or stereoisomer thereof; and a pharmaceutically acceptable diluent or carrier. As used herein, a therapeutically effective dose refers to that amount of the compound or compounds sufficient to result in the prevention or attenuation of a disease or condition as described herein. Techniques for formulation and administration of the compounds of the instant application may be found in references well known to one of ordinary skill in the art, such as "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, latest edition. Suitable routes of administration may, for example, include oral, eyedrop, rectal, transmucosal, topical, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections. Alternatively, one may administer the compound in a local rather than a systemic manner, for example, via injection of the compound directly into an edematous site, often in a depot or sustained release formulation. Furthermore, one may administer the drug in a targeted drug delivery system, for example, in a liposome coated with endothelial cell-specific antibody. The pharmaceutical compositions of the present invention may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. Pharmaceutical compositions for use in accordance with the present invention thus may be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. For injection, the agents of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art. For oral administration, the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained by combining the active compound with a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses. Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration. For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner. For administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch. The compounds can be formulated for parenteral administration by injection, e.g., bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides. In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly or by intramuscular injection). Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt. Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethysulfoxide also may be employed, although usually at the cost of greater toxicity. Additionally, the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed. The pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols. Many of the compounds of the invention may be provided as salts with pharmaceutically compatible counterions (i.e., pharmaceutically acceptable salts). A “pharmaceutically acceptable salt” means any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound or a prodrug of a compound of this invention. A “pharmaceutically acceptable counterion” is an ionic portion of a salt that is not toxic when released from the salt upon administration to a recipient. Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free base forms. Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, as well as organic acids such as para-toluenesulfonic, salicylic, tartaric, bitartaric, ascorbic, maleic, besylic, fumaric, gluconic, glucuronic, formic, glutamic, methanesulfonic, ethanesulfonic, benzenesulfonic, lactic, oxalic, para- bromophenylsulfonic, carbonic, succinic, citric, benzoic and acetic acid, and related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4- dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, .beta.-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like salts. Preferred pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and especially those formed with organic acids such as maleic acid. Suitable bases for forming pharmaceutically acceptable salts with acidic functional groups include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine; tributyl amine; pyridine; N-methyl-N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine, N,N-di alkyl-N-(hydroxy alkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)amine, or tri-(2- hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such as arginine, lysine, and the like. Pharmaceutical compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an effective amount to achieve its intended purpose. More specifically, a therapeutically effective amount means an amount effective to prevent development of or to alleviate the existing symptoms of the subject being treated. Determination of the effective amounts is well within the capability of those skilled in the art. Methods of Use Disclosed herein are compounds and compositions for inhibiting TyrDC, which decarboxylates tyrosine, L-dopa, and related molecules. Enzyme inhibition can be measured using several methods known in the art, such as liquid chromatography-mass spectrometry. Compounds that effectively inhibit TyrDC can be identified using whole cell assays as described herein. Certain disclosed compounds can competitively inhibit TyrDC to inhibit gut microbial metabolism of L-dopa, and could thereby potentially increase bioavailability of L-dopa (FIG.1). Such compounds may be suitable for use in treatment of neurodegenerative diseases such as Parkinson’s Disease, such as by co-administration with L-dopa. In certain preferred embodiments, such compounds are characterized by IC 50 < 1 µM in whole cells and complex gut microbiota. In other preferred embodiments, such compounds are characterized by low blood brain permeability. In other preferred embodiments, such compounds are not suitable for tyrosine hydroxylation (e.g, not reactive toward tyrosine hydroxylation). Disclosed herein are methods of treating Parkinson’s Disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or formula (II): or or a pharmaceutically acceptable salt thereof, wherein, as permitted by valence and stability: X 5 is =N–, –C(O)–, or =C(R 4 )-; R 4 is hydroxyl; methoxy; amino; halogen; hydrogen; -N(R 6 )C(O)R 5 ; or C 1-6 alkyl, optionally substituted with one or more halogen; X 1 is =N–, –N(OH)–, or –C(R 7 )=; X 2 is –N=, –C(O)–, or =C(R 11 )-; X 3 is =N- or =C(R 8 )-; X 4 is =N- or =C(R 12 )-; provided that no more than two of X 1 to X 5 are =N-; and when X 1 is –N(OH)–, one and only one of X 2 and X 5 is –C(O)–; X 6 is =N-, -NR 13 -, or =C(R 7 )-; X 7 is =N-, -NR 13 -, or =C(R 11 )-; X 8 is =N-, -NR 13 -, or =C(R 8 )-; X 10 is =N-, -NR 13 -, or =C(R 4 )-; provided that, if at least three of X 6 to X 10 are =N-, one of X 6 to X 10 is -NR 13 -; R 6 is H or C 1-6 alkyl; R 5 is C 1-6 alkyl; R 11 is hydrogen, halogen, C 1-6 alkyl, amino, or –N(R 6 )C(O)R 5 ; R 12 is hydrogen, halogen, C 1-6 alkyl, amino, or –N(R 6 )C(O)R 5 ; R 7 is hydrogen, hydroxyl, amino, halogen, or –N(R 6 )C(O)R 5 ; R 8 is hydrogen, hydroxyl, amino, halogen, or –N(R 6 )C(O)R 5 ; or R 4 and R 7 , or R 4 and R 8 , or R 7 and R 11 , or R 8 and R 12 , together with the carbon atoms to which they are attached, combine to form a 5- to 6-membered carbocyclic or heterocyclic ring; R 13 is hydrogen, halogen, C 1-6 alkyl, amino, or –N(R 6 )C(O)R 5 ; R 1 is hydrogen or C 1-6 alkyl; R 2 is hydrogen or C 1-6 alkyl; R 3 is –ONR 14 2 , –NHNH 2 , or ; R 14 is, independently at each occurrence, H or C 1-6 alkyl; R 9 is hydrogen or is C 2-6 alkynyl, C 2-6 alkenyl, C 1-6 alkyl, each optionally substituted with one or more halogen, hydroxyl, amino, cyano, or alkoxy; and R 10 is amino, –NHBoc, –ONH 2 , or –NHNH 2 ; or R 2 and R 3 , together with the carbon atom to which they are attached, combine to form . In some embodiments, R 14 is, independently at each occurrence, H or CH 3 . In some embodiments, R 3 is . In some embodiments, R 4 is hydroxyl; amino; halogen; hydrogen; -N(R 6 )C(O)R 5 ; or C 1-6 alkyl, optionally substituted with one or more halogen; R 1 is hydrogen or C 1-6 alkyl; R 2 is hydrogen or C 1-6 alkyl; R 3 is –NHNH 2 , -ONH 2 , or ; and R 10 is amino, -ONH 2 , or –NHNH 2 . In some embodiments, the compound is not: , , or , or a pharmaceutically acceptable salt of any of the foregoing. In some such embodiments, the compound is not or a pharmaceutically acceptable salt thereof. In some such embodiments, the compound of formula (I) is: ,
, or , or a pharmaceutically acceptable salt thereof. In some such embodiments, the compound of formula (I) is , , or , , , or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of formula (I) is not: , , , or a pharmaceutically acceptable salt thereof. Also provided herein are methods of inhibiting a tyrosine decarboxylase (TyrDC), comprising contacting the TyrDC with a compound of formula (I) or formula (II): or or a pharmaceutically acceptable salt thereof, wherein: X 5 is =N–, –C(O)–, or =C(R 4 )-; R 4 is hydroxyl; methoxy; amino; halogen; hydrogen; -N(R 6 )C(O)R 5 ; or C 1-6 alkyl, optionally substituted with one or more halogen; X 1 is =N–, –N(OH)–, or –C(R 7 )=; X 2 is –N=, –C(O)–, or =C(R 11 )-; X 3 is =N- or =C(R 8 )-; X 4 is =N- or =C(R 12 )-; provided that no more than two of X 1 to X 5 are =N-; and when X 1 is –N(OH)–, one and only one of X 2 and X 5 is –C(O)–; X 6 is =N-, -NR 13 -, or =C(R 7 )-; X 7 is =N-, -NR 13 -, or =C(R 11 )-; X 8 is =N-, -NR 13 -, or =C(R 8 )-; X 10 is =N-, -NR 13 -, or =C(R 4 )-; provided that, if at least three of X 6 to X 10 are =N-, one of X 6 to X 10 is -NR 13 -; R 6 is H or C 1-6 alkyl; R 5 is C 1-6 alkyl; R 11 is hydrogen, halogen, C 1-6 alkyl, amino, or –N(R 6 )C(O)R 5 ; R 12 is hydrogen, halogen, C 1-6 alkyl, amino, or –N(R 6 )C(O)R 5 ; R 7 is hydrogen, hydroxyl, amino, halogen, or –N(R 6 )C(O)R 5 ; R 8 is hydrogen, hydroxyl, amino, halogen, or –N(R 6 )C(O)R 5 ; or R 4 and R 7 , or R 4 and R 8 , or R 7 and R 11 , or R 8 and R 12 , together with the carbon atoms to which they are attached, combine to form a 5- to 6-membered carbocyclic or heterocyclic ring; R 13 is hydrogen, halogen, C 1-6 alkyl, amino, or –N(R 6 )C(O)R 5 ; R 1 is hydrogen or C 1-6 alkyl; R 2 is hydrogen or C1 -6 alkyl; R 3 is –ONR 14 2 , –NHNH 2 , or ; R 14 is, independently at each occurrence, H or C 1-6 alkyl; R 9 is hydrogen or is C 2-6 alkynyl, C 2-6 alkenyl, C 1-6 alkyl, each optionally substituted with one or more halogen, hydroxyl, amino, cyano, or alkoxy; and R 10 is amino, –NHBoc, –ONH 2 , or –NHNH 2 ; or R 2 and R 3 , together with the carbon atom to which they are attached, combine to form . In some embodiments, R 14 is, independently at each occurrence, H or CH 3 . In some embodiments, R 3 is . In some embodiments, R 4 is hydroxyl; amino; halogen; hydrogen; -N(R 6 )C(O)R 5 ; or C 1-6 alkyl, optionally substituted with one or more halogen; R 1 is hydrogen or C 1-6 alkyl; R 2 is hydrogen or C 1-6 alkyl; R 3 is –NHNH 2 , -ONH 2 , or ; and R 10 is amino, -ONH 2 , or –NHNH 2 . In some embodiments, the compound is not , , or . In some such embodiments, the compound is not . In some embodiments, the compound of formula (I) is: , ,
, or , , or , or a pharmaceutically acceptable salt thereof. In some such embodiments, the compound of formula (I) is
, , or , or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of formula (I) is not: , , , , , or a pharmaceutically acceptable salt thereof. In some embodiments, the TyrDC is Enterococcus faecalis TyrDC, Enterococcus faecium TyrDC, or Providencia rettgeri TyrDC. Exemplary strains of E. faecalis include, but are not limited to, E. faecalis OG1RF, E. faecalis V1583, E. faecalis TX0104, and E. faecalis MMH594. Exemplary strains of E. faecium include, but are not limited to, E. faecium E1007, E. faecium E2134, and E. faecium TX1330. Also provided herein are methods of treating Parkinson’s Disease in a subject in need thereof, comprising ad ministering to the subject a therapeutically effective amount of a compound of formula (Ia): or a pharmaceutically acceptable salt thereof, wherein: X 5 is N or CR 4 ; R 4 is hydroxyl; methoxy; amino; halogen; hydrogen; -N(R 6 )C(O)R 5 ; or C 1-6 alkyl, optionally substituted with one or more halogen; X 1 is N or CR 7 ; X 2 is N or CR 11 ; X 3 is N or CR 8 ; X 4 is N or CR 12 ; provided that no more than two of X 1 to X 5 are N; R 6 is H or C 1-6 alkyl; R 5 is C 1-6 alkyl; R 11 is hydrogen, halogen, or C 1-6 alkyl; R 12 is hydrogen, halogen, or C 1-6 alkyl; R 7 is hydrogen, hydroxyl, amino, or halogen; R 8 is hydrogen, hydroxyl, amino, or halogen; or R 4 and R 7 , or R 4 and R 8 , together with the carbon atoms to which they are attached, combine to form a 5- to 6-membered carbocyclic or heterocyclic ring; R 1 is hydrogen or C 1-6 alkyl; R 2 is hydrogen or C 1-6 alkyl; R 3 is –ONR 14 2 , –NHNH 2 , or ; R 14 is, independently at each occurrence, H or C 1-6 alkyl; R 9 is hydrogen or is C 2-6 alkynyl, C 2-6 alkenyl, C 1-6 alkyl, each optionally substituted with one or more halogen, hydroxyl, amino, cyano, or alkoxy; and R 10 is amino, –NHBoc, –ONH 2 , or –NHNH 2 ; or R 2 and R 3 , together with the carbon atom to which they are attached, combine to form . In some embodiments, R 14 is, independently at each occurrence, H or CH 3 . In some embodiments, wherein R 3 is . In some embodiments, R 4 is hydroxyl; amino; halogen; hydrogen; -N(R 6 )C(O)R 5 ; or C 1-6 alkyl, optionally substituted with one or more halogen; R 1 is hydrogen or C 1-6 alkyl; R 2 is hydrogen or C 1-6 alkyl; R 3 is–NHNH 2 , -ONH 2 , or ; R 10 is amino, -ONH 2 , or -NHNH 2 . In some embodiments, the compound is not , , or , or a pharmaceutically acceptable salt thereof. In some such embodiments, the compound is not or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (Ia) is: ,
, , or , or a pharmaceutically acceptable salt thereof. In some such embodiments, the compound of formula (Ia) is , , or , or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of formula (Ia) is not: , , or a pharmaceutically acceptable salt thereof. Also provided herein are methods of inhibiting a tyrosine decarboxylase (TyrDC) comprising contacting the TyrDC with a compound of formula (Ia): or a pharmaceutically acceptable salt thereof, wherein: X 5 is N or CR 4 ; R 4 is hydroxyl; methoxy; amino; halogen; hydrogen; -N(R 6 )C(O)R 5 ; or C 1-6 alkyl, optionally substituted with one or more halogen; X 1 is N or CR 7 ; X 2 is N or CR 11 ; X 3 is N or CR 8 ; X 4 is N or CR 12 ; provided that no more than two of X 1 to X 5 are N; R 6 is H or C 1-6 alkyl; R 5 is C 1-6 alkyl; R 11 is hydrogen, halogen, or C 1-6 alkyl; R 12 is hydrogen, halogen, or C 1-6 alkyl; R 7 is hydrogen, hydroxyl, amino, or halogen; R 8 is hydrogen, hydroxyl, amino, or halogen; or R 4 and R 7 , or R 4 and R 8 , together with the carbon atoms to which they are attached, combine to form a 5- to 6-membered carbocyclic or heterocyclic ring; R 1 is hydrogen or C 1-6 alkyl; R 2 is hydrogen or C 1-6 alkyl; R 3 is -ONR 14 2 , –NHNH 2 , or ; R 14 is, independently at each occurrence, H or C 1-6 alkyl; R 9 is hydrogen or is C 2-6 alkynyl, C 2-6 alkenyl, C 1-6 alkyl, each optionally substituted with one or more halogen, hydroxyl, amino, cyano, or alkoxy; and R 10 is amino, -NHBoc, –ONH 2 , or –NHNH 2 ; or R 2 and R 3 , together with the carbon atom to which they are attached, combine to form . In some embodiments, R 14 is, independently at each occurrence, H or CH 3 . In some embodiments, R 3 is . In some embodiments, R 4 is hydroxyl; amino; halogen; hydrogen; -N(R 6 )C(O)R 5 ; or C 1-6 alkyl, optionally substituted with one or more halogen; R 1 is hydrogen or C 1-6 alkyl; R 2 is hydrogen or C 1-6 alkyl; R 3 is –NHNH 2 , -ONH 2 , or ; R 10 is amino, -ONH 2 , or –NHNH 2 . In some embodiments, the compound of formula (Ia) is not , , or , or a pharmaceutically acceptable salt thereof. In some such embodiments, the compound of formula (Ia) is not or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (Ia) is , ,
, , or , or a pharmaceutically acceptable salt thereof. In some such embodiments, the compound of formula (Ia) is , , or , or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of formula (Ia) is not: , , or a pharmaceutically acceptable salt thereof. In some embodiments, the TyrDC is Enterococcus faecalis TyrDC, Enterococcus faecium TyrDC, or Providencia rettgeri TyrDC. Exemplary strains of E. faecalis include, but are not limited to, E. faecalis OG1RF, E. faecalis V1583, E. faecalis TX0104, and E. faecalis MMH594. Exemplary strains of E. faecium include, but are not limited to, E. faecium E1007, E. faecium E2134, and E. faecium TX1330. EXEMPLIFICATION The invention now being generally described, it will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention.
Scaffold Design Employing small molecules to inhibit the activity of microbial TyrDC toward L- dopa has the potential to improve L-dopa therapy for Parkinson’s disease patients. The discovery of α-fluoromethyltyrosine (AFMT) as an inhibitor of L-dopa decarboxylation by the TyrDC-expressing bacterium E. faecalis led us to seek novel inhibitors with improved potency and selectivity. We have investigated: (1) the aromatic scaffold and (2) the nucleophilic warhead that engages the pyridoxal phosphate (PLP) cofactor of TyrDC (FIGS.2A-2C). Identification of Aromatic Scaffolds for TyrDC Inhibitor TyrDC exhibits a preference for substrates that resemble tyrosine. Indeed, tyrosine or L-dopa undergoes decarboxylation in whole cells at a faster rate in comparison to m- tyrosine. AFMT was shown to be a potent TyrDC inhibitor in whole cells (EC 50 = 1.4 μM). Thus, this project set out to more fully assess the potential for further substitution of the aromatic ring. The current synthesis of AFMT is linear, lengthy, and limited in scope. We have developed a divergent synthetic strategy for the construction of AFMT analogs (vide infra). To more rapidly assess tolerance of the enzyme (and cellular transporters) to different substituents on the aromatic ring of tyrosine, we chose to employ the native decarboxylation activity of TyrDC as a structural probe to survey a wide range of tyrosine analogs. Tyrosine analogs are readily available via commercial and synthetic sources, which renders a high throughput approach feasible. Thus, a library of commercially available tyrosine and phenylalanine derivatives were evaluated for decarboxylation by Enterococcus faecalis MMH594 whole cells; decarboxylation efficiency of a given tyrosine analog was used to identify favorable aromatic fragments, with high conversion indicating a favorable arene scaffold. We observed that decarboxylation was most effective when a hydroxyl group was present at the para position, and that substitutions at other positions on the arene were well tolerated as long as this para-hydroxyl group was present (FIG.3A). To quickly assess whether the trend in native decarboxylation activity can be translated to inhibitory activity, we evaluated benzyl aminooxy compounds with similar aromatic elements as inhibitors for L- dopa decarboxylation in E. faecalis MMH594 whole cells (10 µM inhibitor); high L-dopa recovery indicated high inhibitory efficiency. Studies have demonstrated benzyl aminooxy compounds are inhibitors for PLP-dependent decarboxylase enzymes. In addition, these compounds are either commercially available or can be accessed in a two-step synthetic sequence (European Journal of Medicinal Chemistry 2016, 108, 564-576). As shown, inhibitors without a para-hydroxyphenyl motif are not effective towards L-dopa decarboxylation in whole cells (FIG.3B). Aminooxy compounds with this structural motif can inhibit L-dopa decarboxylation in E. faecalis cultures at low concentrations. Notably, the potency of 4-hydroxybenzyl aminooxy and 3-fluoro-4-hydroxybenzyl aminooxy compounds were similar to AFMT, with EC50 values of 1.5 μM and 2.2 μM, respectively (FIG.3C). Divergent Synthesis of Tyrosine Analogs by Photocatalysis Tyrosine analogs were prepared by applying the conditions provided in JACS 2016, 138, 8084-8087, which couples alkyl bromides with aryl or heteroaryl bromides. The alkyl bromide can be prepared directly in decagram scale from a protected serine. While unprotected heterobromoarenes such as , and did not afford the desired product, methyl-protected substrates such as , and yielded the desired coupling products. Additional heterobromoarenes to be tested in the coupling reaction include , a nd . Tyrosine Analog Decarboxyation Activity We also examined the efficiency with which E. faecalis MMH594 decarboxylates these new unnatural amino acids (FIG.4). Substrate (500 µM) was incubated with E. faecalis WT MMH594 in BHI media under anaerobic conditions at 37°C for 18-24 hours (done in triplicate). The amount of remaining starting material was analyzed by LC-MS- MRM. Results were normalized to samples incubated with E. faecalis ΔtyrDC3. We observed that substitution of the p-hydroxyl substituent of L-Tyr with a difluoromethyl group limits the decarboxylation efficiency, suggesting that inhibitors with this bioisosteric substituent would not be as effective as those bearing native 4-hydroxyphenyl group. In addition, the 2-hydroxypyridyl analog was tolerated, being converted to the corresponding amine to to tyrosine, in low efficiency. AFMT Analog Synthesis Synthesis of α-fluoromethyl amino acids has typically been a laborious process. We have investigated different strategies to establish a shorter and more robust route to synthesize AFMT analogs. Recently, we found a relatively quick process that converts the amino acid to its corresponding α-fluoromethyl analog. As shown below, p- methoxyphenylalanine (8) was converted to the oxazolidinone 9 to facilitate the hydroxymethyl motif installation. The key deoxyfluorination step was examined under different reported protocols. AlkylFluor was effective in giving the desired product 12 in acceptable yield. Deprotection of alkyl fluoride 12 should yield the corresponding α- fluoromethylamino acids. Protocols for deprotection of alkyl fluorides such as 12 are well established. Overall, the sequence comprises robust transformations that do not require specialized reaction apparatus.
Inhibitory Effect of AFMT Analogs AFMT analogs were evaluated for their inhibitory effects towards L-dopa decarboxylation using the same protocol as described above.500 µM L-dopa was incubated anaerobically at 37 °C with E. faecalis MMH594 in the presence of 100 µM inhibitor for 18-24h. The level of remaining L-dopa was measured by MS/MS and then normalized to the level of L-dopa from a mutant control. As shown in FIG.5, EPB-TDC-021, -031, -041, and -062 were found to retain >80% of L-dopa. Since (S)-AFMT is the active AFMT enantiomer, the stereochemical assignments in FIG.5 assume that the enantiomer with the higher inhibitory activity carries the (S) configuration. Chiral configuration will be unambiguously determined via crystallography in the future. Fluoride substituents are well-tolerated on the aromatic motif, as shown by EPB- TDC-021 and -062. In addition, the activity of EPB-TDC-41 suggests that a meta-hydroxyl group can be similarly effective to its para- counterpart, and comparing the activity of AFMT, EPB-TDC-031, and -041 to -051/-052 suggests the importance of a hydroxyl group for inhibitory activity. These results also show the importance of the nucleophilic warhead in inhibitor design. In our original study, carbidopa was found to be ineffective in limiting L-dopa decarboxylation by E. faecalis. Comparing carbidopa with EPB-TDC-031 shows that the α- fluoromethyl warhead in 031 is more effective than the α-methyl-hydrazine of carbidopa. Furthermore, the comparison between AFMT and EPB-TDC-071 revealed that the α- fluoromethyl moiety is more effective in comparison to the α-difluoromethyl warhead. Assessing Inhibitor Effects on L-dopa Bioavailability Preliminary mouse experiments to examine the efficacy of AFMT in increasing serum L-dopa levels support a correlation between this effect and TyrDC inhibition. As shown in FIG.6, gnotobiotic mice will be colonized with either E. faecalis MMH594 WT or E. faecalist MMH594 mutant wherein tyrDC is interrupted by a Tet-cassette. For each group, a cocktail of AFMT/L-dopa/carbidopa or the corresponding vehicle control will be administered. The L-dopa concentration in the serum will be monitored periodically. A comparison of serum L-dopa concentrations in the WT group will provide supporting evidence for the effect of AFMT on the bioavailability of L-dopa. Next, a comparison between the WT and mutant groups will provide an indication that the increase in L-dopa levels is due to inhibiting E. faecalis L-dopa metabolism by TyrDC. The results of this initial experiment may inform follow up experiments to optimize the dosing of AFMT and will also inform experiments on subsequent generations of inhibitors. After efficacy and safety of AFMT and other inhibitors has been assessed, studies will begin with an animal model of Parkinson’s disease. Specifically, changes in serum and brain L-dopa levels will be assessed in parallel to motor function in the animals. Incorporation by Reference All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control. Equivalents While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.