Title:
CYCLIN GROOVE INHIBITORS
Document Type and Number:
WIPO Patent Application WO2005042565
Kind Code:
A3
Abstract:
The present invention relates to a compound of formula (I), or a variant thereof, A - (B)m - C - (D)n- E, wherein m and n are each independently 0 or 1 and A, B, C, D and E are each independently linked to the respective adjacent residue by a linker group independently selected from carboxamide, reduced carboxamide, sulfonamide, imine, semicarbazone, oxime and ethanolamine; A is (i) a natural or unnatural amino acid residue having a side chain comprising at least one H-bond acceptor moiety and at least one H-bond donor moiety, or a derivative thereof; or (ii) R(CO), wherein R is a C1-C24 hydrocarbyl group comprising at least one H-bond acceptor moiety and optionally one or more H-bond donor moieties, and where R optionally contains one or more heteroatoms selected from S, O, and N, and is optionally substituted by one or more substituents selected from halogen, OMe, CN, CF3, and NO2; each of B and D is independently an amino acid residue selected from arginine, 4-(guanidinyl)phenylalanine (4-(Gu)Phe), piperidinylglycine (PipGly), piperidinylalanine (PipAla), pyridinylalanine, histamine, N,N-(dimethyl) lysine (DMLys), citrulline, glutamine, serine, lysine, asparagine, isoleucine and alanine, or a derivative thereof; C is NH-X-CO, where X is a C1-C4 alkylene group substituted by a straight-chain or branched C1-C6 alkylene group, said C1-C6 alkylene group optionally containing a H-bond donor or H-bond acceptor moiety; E is (i) a natural or unnatural amino acid residue having an aryl or heteroaryl side chain, or a derivative thereof; or (ii) NHR', where R' is a C1-C24 hydrocarbyl group, optionally containing one or more heteroatoms selected from N, O, and S, and optionally comprising one or more H-bond acceptor or donor moieties; said hydrocarbyl group further comprising a pendent C4-C12 aryl or heteroaryl group, which itself may be optionally substituted by one or more substituents selected from a H-bond donor moiety, a H-bond acceptor moiety, a halogen, Me, Et, Pr, CF3, CN and NO2; wherein at least one of A and E is other than a natural or unnatural amino acid residue when A, B, C, D and E are each linked to the respective adjacent residue by a carboxamide group.
Inventors:
ANDREWS MARTIN J I (GB)
MCINNES CAMPBELL (GB)
KONTOPIDIS GEORGE (GB)
FISCHER PETER M (GB)
MCINNES CAMPBELL (GB)
KONTOPIDIS GEORGE (GB)
FISCHER PETER M (GB)
Application Number:
PCT/GB2004/004454
Publication Date:
August 11, 2005
Filing Date:
October 21, 2004
Export Citation:
Assignee:
CYCLACEL LTD (GB)
ANDREWS MARTIN J I (GB)
MCINNES CAMPBELL (GB)
KONTOPIDIS GEORGE (GB)
FISCHER PETER M (GB)
ANDREWS MARTIN J I (GB)
MCINNES CAMPBELL (GB)
KONTOPIDIS GEORGE (GB)
FISCHER PETER M (GB)
International Classes:
C07K14/47; G01N33/50; G01N33/68; A61K38/00; (IPC1-7): C07K5/00; C07K5/02; C07K7/00; C07K7/02; A61K38/00; G01N33/68; G01N33/574; G06F19/00
Domestic Patent References:
| WO2001040142A2 | 2001-06-07 |
Other References:
GREGORY, HAROLD ET AL: "Polypeptides. VII. Variations of the phenylalanyl position in the C-termial tetrapeptide amide sequence of the gastrins", JOURNAL OF THE CHEMICAL SOCIETY [SECTION] C: ORGANIC , (5), 531-40 CODEN: JSOOAX; ISSN: 0022-4952, 1968, XP002126865
SAKINA K ET AL: "THERMOLYSIN-CATALYZED SYNTHESIS OF PEPTIDE AMIDES", CHEMICAL AND PHARMACEUTICAL BULLETIN, vol. 36, no. 11, 1988, TOKYO, pages 4345 - 4354, XP001204782, ISSN: 0009-2363
MCINNES CAMPBELL ET AL: "Peptidomimetic design of CDK inhibitors targeting the recruitment site of the cyclin subunit.", CURRENT MEDICINAL CHEMISTRY - ANTI-CANCER AGENTS, vol. 3, no. 1, January 2003 (2003-01-01), pages 57 - 69, XP009042742, ISSN: 1568-0118
FISCHER P M ET AL: "INHIBITORS OF CYCLIN-DEPENDENT KINASES AS ANTI-CANCER THERAPEUTICS", CURRENT MEDICINAL CHEMISTRY, vol. 7, no. 12, December 2000 (2000-12-01), BENTHAM SCIENCE PUBLISHERS BV, BE, pages 1213 - 1245, XP002314047, ISSN: 0929-8673
KONTOPIDIS, GEORGE ET AL: "Insights into Cyclin Groove Recognition: Complex Crystal Structures and Inhibitor Design through Ligand Exchange", STRUCTURE, CODEN: STRUE6; ISSN: 0969-2126, vol. 11, no. 12, December 2003 (2003-12-01), CAMBRIDGE, MA, UNITED STATES, pages 1537 - 1546, XP002313908
SAKINA K ET AL: "THERMOLYSIN-CATALYZED SYNTHESIS OF PEPTIDE AMIDES", CHEMICAL AND PHARMACEUTICAL BULLETIN, vol. 36, no. 11, 1988, TOKYO, pages 4345 - 4354, XP001204782, ISSN: 0009-2363
MCINNES CAMPBELL ET AL: "Peptidomimetic design of CDK inhibitors targeting the recruitment site of the cyclin subunit.", CURRENT MEDICINAL CHEMISTRY - ANTI-CANCER AGENTS, vol. 3, no. 1, January 2003 (2003-01-01), pages 57 - 69, XP009042742, ISSN: 1568-0118
FISCHER P M ET AL: "INHIBITORS OF CYCLIN-DEPENDENT KINASES AS ANTI-CANCER THERAPEUTICS", CURRENT MEDICINAL CHEMISTRY, vol. 7, no. 12, December 2000 (2000-12-01), BENTHAM SCIENCE PUBLISHERS BV, BE, pages 1213 - 1245, XP002314047, ISSN: 0929-8673
KONTOPIDIS, GEORGE ET AL: "Insights into Cyclin Groove Recognition: Complex Crystal Structures and Inhibitor Design through Ligand Exchange", STRUCTURE, CODEN: STRUE6; ISSN: 0969-2126, vol. 11, no. 12, December 2003 (2003-12-01), CAMBRIDGE, MA, UNITED STATES, pages 1537 - 1546, XP002313908
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