Title:
NOVEL VASCULAR LEAK INHIBITOR
Document Type and Number:
WIPO Patent Application WO/2011/053048
Kind Code:
A2
Abstract:
The present invention relates to a novel vascular leak inhibitor. The novel vascular leak inhibitor of the present invention inhibits the apoptosis of vascular endothelial cells, inhibits the formation of actin stress fibers induced by VEGF, increases a cortical actin ring structure, and improves the stability of the tight junctions (TJ) among vascular cells, thereby inhibiting vascular leak. The vascular leak inhibitor of the present invention has the activity of not only inhibiting vascular permeability, but also of recovering the integrity of damaged blood vessels. Accordingly, the vascular leak inhibitor of the present invention can prevent or treat various diseases caused by vascular leak. The vascular leak inhibitor of the present invention is a substance which has high commercial availability and which enables easy synthesis. The vascular leak inhibitor of the present invention is synthesized using cholesterols as a parent nucleus, and therefore has remarkably superior feasibility of commercial synthesis.
Inventors:
KWON YOUNG-GUEN (KR)
SUH YOUNG-GER (KR)
SUH YOUNG-GER (KR)
Application Number:
PCT/KR2010/007533
Publication Date:
May 05, 2011
Filing Date:
October 29, 2010
Export Citation:
Assignee:
UNIV YONSEI IACF (KR)
KWON YOUNG-GUEN (KR)
SUH YOUNG-GER (KR)
KWON YOUNG-GUEN (KR)
SUH YOUNG-GER (KR)
International Classes:
C07D309/02; A61K31/35; A61P9/00; C07D309/04
Domestic Patent References:
| WO1997018816A2 | 1997-05-29 |
Other References:
"Remington's Pharmaceutical Sciences", 1995
TETRAHEDRON LETT., vol. 31, 1990, pages 7441 - 7444
SYNTHESIS, vol. 22, 2008, pages 3619 - 3624
J. ORG. CHEM., vol. 44, 1979, pages 3760 - 3765
MOSMANN T, JOURNAL OF IMMUNOLOGICAL METHODS, vol. 65, no. 1-2, 1983, pages 55 - 63
CORY AH ET AL., CANCER COMMUNICATIONS, vol. 3, no. 7, 1991, pages 207 - 12
ERICKSON KK; SUNDSTROM JM; ANTONETTI DA: "Vascular permeability in ocular disease and the role of tight junctions", ANGIOGENESIS, vol. 10, no. 2, 2007, pages 103 - 17
MANIATIS NA; ORFANOS SE: "The endothelium in acute lung injury/acute respiratory distress syndrome", CURR OPIN CRIT CARE, vol. 14, no. 1, February 2008 (2008-02-01), pages 22 - 30
HARHAJ NS; ANTONETTI DA: "Regulation of tight junctions and loss of barrier function in pathophysiology", INT J BIOCHEM CELL BIOL., vol. 36, no. 7, July 2004 (2004-07-01), pages 1206 - 37
VANDENBROUCKE E; MEHTA D; MINSHALL R; MALIK AB: "Regulation of endothelial junctional permeability", ANN N YACAD SCI., vol. 1123, March 2008 (2008-03-01), pages 134 - 45
D'ATRI F; HAMMAR E ET AL.: "Cingulin contains globular and coiled-coil domains and interacts with ZO-1, ZO-2, ZO-3, and myosin", J CELL BIOL., vol. 147, no. 7, 27 December 1999 (1999-12-27), pages 1569 - 82
HASKINS J; GU L; WITTCHEN ES; HIBBARD J; STEVENSON BR: "ZO-3, a novel member of the MAGUK protein family found at the tight junction, interacts with ZO-1 and occludin", J CELL BIOI., vol. 141, no. 1, 6 April 1998 (1998-04-06), pages 199 - 208
ITOH M; FURUSE M; MORITA K; KUBOTA K; SAITOU M; TSUKITA S: "Direct binding of three tight junction-associated MAGUKs, ZO-1, ZO-2, and ZO-3, with the COOH termini of claudins", J CELL BIOL., vol. 147, no. 6, 13 December 1999 (1999-12-13), pages 1351 - 63
MADARA JL: "Regulation of the movement of solutes across tight junctions", ANNU REV PHYSIOL., vol. 60, 1998, pages 143 - 59
ANDERSON JM; VAN ITALLIE CM.: "Tight junctions and the molecular basis for regulation of paracellular permeability", AM J PHYSIOL., vol. 269, October 1995 (1995-10-01), pages G467 - 75
MEHTA D; MALIK AB.: "Signaling mechanisms regulating endothelial permeability", PHYSIOL REV., vol. 86, no. 1, January 2006 (2006-01-01), pages 279 - 367
MCVERRY BJ; GARCIA JG.: "Endothelial cell barrier regulation by sphingosine 1-phosphate", J CELL BIOCHEM., vol. 92, no. 6, 15 August 2004 (2004-08-15), pages 1075 - 85
GARCIA JG; LIU F; VERIN AD ET AL.: "Sphingosine 1-phosphate promotes endothelial cell barrier integrity by Edg-dependent cytoskeletal rearrangement", J CLIN INVEST., vol. 108, no. 5, September 2001 (2001-09-01), pages 689 - 701
DUDEK SM; JACOBSON JR; CHIANG ET ET AL.: "Pulmonary endothelial cell barrier enhancement by sphingosine 1-phosphate: roles for cortactin and myosin light chain kinase", J BIOL CHEM., vol. 279, no. 23, 4 June 2004 (2004-06-04), pages 24692 - 700
WEED SA; PARSONS JT: "Cortactin: coupling membrane dynamics to cortical actin assembly", ONCOGENE, vol. 20, no. 44, 1 October 2001 (2001-10-01), pages 6418 - 34
SACHA E.: "Diabetic retinopathy. Current opinion on pathophysiology, diagnostics and therapy", PRZEGL LEK., vol. 62, no. 4, 2005, pages 238 - 42
FRANK RN.: "Diabetic retinopathy", N ENGL J MED., vol. 350, no. 1, 1 January 2004 (2004-01-01), pages 48 - 58
GARIANO RF; GARDNER TW.: "Retinal angiogenesis in development and disease", NATURE, vol. 438, no. 7070, 15 December 2005 (2005-12-15), pages 960 - 6
MURATA T; ISHIBASHI T; KHALIL A; HATA Y; YOSHIKAWA H; INOMATA H: "Vascular endothelial growth factor plays a role in hyperpermeability of diabetic retinal vessels", OPHTHALMIC RES., vol. 27, no. 1, 1995, pages 48 - 52
WEIS SM; CHERESH DA: "Pathophysiological consequences of VEGF-induced vascular permeability", NATURE, vol. 437, no. 7058, 22 September 2005 (2005-09-22), pages 497 - 504
KIEFER D; PANTUSO T.: "Panax ginseng", AM FAM PHYSICIAN, vol. 68, no. 8, 15 October 2003 (2003-10-15), pages 1539 - 42
LEE TK; JOHNKE RM; ALLISON RR; O'BRIEN KF; DOBBS U, JR.: "Radioprotective potential of ginseng", MUTAGENESIS, vol. 20, no. 4, July 2005 (2005-07-01), pages 237 - 43
KWON SW; HAN SB; PARK IH; KIM JM; PARK MK; PARK JH.: "Liquid chromatographic determination of less polar ginsenosides in processed ginseng", J CHROMATOGR A., vol. 921, no. 2, 6 July 2001 (2001-07-06), pages 335 - 9
KEUM YS; PARK KK; LEE JM ET AL.: "Antioxidant and anti-tumor promoting activities of the methanol extract of heat-processed ginseng", CANCER LETT., vol. 150, no. 1, 13 March 2000 (2000-03-13), pages 41 - 8
BROWNLEE M; CERAMI A; VLASSARA H: "Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications", N ENGL J MED., vol. 318, no. 20, 19 May 1988 (1988-05-19), pages 1315 - 21
BONNARDEL-PHU E; WAUTIER JL; SCHMIDT AM; AVILA C; VICAUT E: "Acute modulation of albumin microvascular leakageage by advanced glycation end products in microcirculation of diabetic rats in vivo", DIABETES, vol. 48, no. 10, October 1999 (1999-10-01), pages 2052 - 8
WOJCIAK-STOTHARD B; RIDLEY AJ: "Rho GTPases and the regulation of endothelial permeability", VASCUL PHARMACOL., vol. 39, no. 4-5, November 2002 (2002-11-01), pages 187 - 99
MIKI H; YAMAGUCHI H; SUETSUGU S; TAKENAWA T.: "IRSp53 is an essential intermediate between Rac and WAVE in the regulation of membrane ruffling", NATURE, vol. 408, no. 6813, 7 December 2000 (2000-12-07), pages 732 - 5
WU NZ; BALDWIN AL.: "Transient venular permeability increase and endothelial gap formation induced by histamine", AM J PHYSIOL., vol. 262, April 1992 (1992-04-01), pages H1238 - 47
EHRINGER WD; EDWARDS MJ; MILLER FN.: "Mechanisms of Alptha-thrombin, histamine, and bradykinin induced endothelial permeability", J CELL PHYSIOL., vol. 167, no. 3, June 1996 (1996-06-01), pages 562 - 9
WOJCIAK-STOTHARD B; POTEMPA S; EICHHOLTZ T; RIDLEY AJ.: "Rho and Rac but not Cdc42 regulate endothelial cell permeability", J CELL SCI., vol. 114, April 2001 (2001-04-01), pages 1343 - 55
YUN TK.: "Experimental and epidemiological evidence on non-organ specific cancer preventive effect of Korean ginseng and identification of active compounds", MUTAT RES., vol. 523-524, February 2003 (2003-02-01), pages 63 - 74
SENGUPTA S; TOH SA; SELLERS LA ET AL.: "Modulating angiogenesis: the yin and the yang in ginseng", CIRCULATION, vol. 110, no. 10, 7 September 2004 (2004-09-07), pages 1219 - 25
YUE PY; WONG DY; WU PK ET AL.: "The angiosuppressive effects of 20(R)- ginsenoside Rg3", BIOCHEM PHARMACOL., vol. 72, no. 4, 14 August 2006 (2006-08-14), pages 437 - 45
SATO K; MOCHIZUKI M; SAIKI I; YOO YC; SAMUKAWA K; AZUMA I.: "Inhibition of tumor angiogenesis and metastasis by a saponin of Panax ginseng, ginsenoside-Rb2", BIOL PHARM BULL., vol. 17, no. 5, May 1994 (1994-05-01), pages 635 - 9
LEUNG KW ET AL.: "Ginsenoside Rb1 inhibits tube-like structure formation of endothelial cells by regulating pigment epithelium-derived factor through the oestrogen beta receptor", BR J PHARMACOL., vol. 152, no. 2, September 2007 (2007-09-01), pages 207 - 15
MIN JK; KIM JH; CHO YL ET AL.: "20(S)-Ginsenoside Rg3 prevents endothelial cell apoptosis via inhibition of a mitochondrial caspase pathway", BIOCHEM BIOPHYS RES COMMUN., vol. 349, no. 3, 27 October 2006 (2006-10-27), pages 987 - 94
PAPAPETROPOULOS A.: "A ginseng-derived oestrogen receptor beta (ERbeta) agonist, Rbl ginsenoside, attenuates capillary morphogenesis", BR J PHARMACOL., vol. 152, no. 2, September 2007 (2007-09-01), pages 172 - 4
MICHEL CC; CURRY FE., PHYSIOL REV., vol. 79, no. 3, July 1999 (1999-07-01), pages 703 - 61
DUDEK SM; GARCIA JG.: "Cytoskeletal regulation of pulmonary vascular permeability", JAPPL PHYSIOL., vol. 91, no. 4, October 2001 (2001-10-01), pages 1487 - 500
GARCIA JG; SIFLINGER-BIRNBOIM A; BIZIOS R; DEL VECCHIO PJ; FENTON JW; MALIK AB.: "Thrombin-induced increase in albumin permeability across the endothelium", J CELL PHYSIOL., vol. 128, no. 1, July 1986 (1986-07-01), pages 96 - 104
LIU F; SCHAPHORST KL; VERIN AD ET AL.: "Hepatocyte growth factor enhances endothelial cell barrier function and cortical cytoskeletal rearrangement: potential role of glycogen synthase kinase-3beta", FASEB J., vol. 16, no. 9, July 2002 (2002-07-01), pages 950 - 62
ZENG L; XU H; CHEW TL ET AL.: "HMG CoA reductase inhibition modulates VEGF-induced endothelial cell hyperpermeability by preventing RhoA activation and myosin regulatory light chain phosphorylation", FASEBJ., vol. 19, no. 13, November 2005 (2005-11-01), pages 1845 - 7
See also references of EP 2495242A4
TETRAHEDRON LETT., vol. 31, 1990, pages 7441 - 7444
SYNTHESIS, vol. 22, 2008, pages 3619 - 3624
J. ORG. CHEM., vol. 44, 1979, pages 3760 - 3765
MOSMANN T, JOURNAL OF IMMUNOLOGICAL METHODS, vol. 65, no. 1-2, 1983, pages 55 - 63
CORY AH ET AL., CANCER COMMUNICATIONS, vol. 3, no. 7, 1991, pages 207 - 12
ERICKSON KK; SUNDSTROM JM; ANTONETTI DA: "Vascular permeability in ocular disease and the role of tight junctions", ANGIOGENESIS, vol. 10, no. 2, 2007, pages 103 - 17
MANIATIS NA; ORFANOS SE: "The endothelium in acute lung injury/acute respiratory distress syndrome", CURR OPIN CRIT CARE, vol. 14, no. 1, February 2008 (2008-02-01), pages 22 - 30
HARHAJ NS; ANTONETTI DA: "Regulation of tight junctions and loss of barrier function in pathophysiology", INT J BIOCHEM CELL BIOL., vol. 36, no. 7, July 2004 (2004-07-01), pages 1206 - 37
VANDENBROUCKE E; MEHTA D; MINSHALL R; MALIK AB: "Regulation of endothelial junctional permeability", ANN N YACAD SCI., vol. 1123, March 2008 (2008-03-01), pages 134 - 45
D'ATRI F; HAMMAR E ET AL.: "Cingulin contains globular and coiled-coil domains and interacts with ZO-1, ZO-2, ZO-3, and myosin", J CELL BIOL., vol. 147, no. 7, 27 December 1999 (1999-12-27), pages 1569 - 82
HASKINS J; GU L; WITTCHEN ES; HIBBARD J; STEVENSON BR: "ZO-3, a novel member of the MAGUK protein family found at the tight junction, interacts with ZO-1 and occludin", J CELL BIOI., vol. 141, no. 1, 6 April 1998 (1998-04-06), pages 199 - 208
ITOH M; FURUSE M; MORITA K; KUBOTA K; SAITOU M; TSUKITA S: "Direct binding of three tight junction-associated MAGUKs, ZO-1, ZO-2, and ZO-3, with the COOH termini of claudins", J CELL BIOL., vol. 147, no. 6, 13 December 1999 (1999-12-13), pages 1351 - 63
MADARA JL: "Regulation of the movement of solutes across tight junctions", ANNU REV PHYSIOL., vol. 60, 1998, pages 143 - 59
ANDERSON JM; VAN ITALLIE CM.: "Tight junctions and the molecular basis for regulation of paracellular permeability", AM J PHYSIOL., vol. 269, October 1995 (1995-10-01), pages G467 - 75
MEHTA D; MALIK AB.: "Signaling mechanisms regulating endothelial permeability", PHYSIOL REV., vol. 86, no. 1, January 2006 (2006-01-01), pages 279 - 367
MCVERRY BJ; GARCIA JG.: "Endothelial cell barrier regulation by sphingosine 1-phosphate", J CELL BIOCHEM., vol. 92, no. 6, 15 August 2004 (2004-08-15), pages 1075 - 85
GARCIA JG; LIU F; VERIN AD ET AL.: "Sphingosine 1-phosphate promotes endothelial cell barrier integrity by Edg-dependent cytoskeletal rearrangement", J CLIN INVEST., vol. 108, no. 5, September 2001 (2001-09-01), pages 689 - 701
DUDEK SM; JACOBSON JR; CHIANG ET ET AL.: "Pulmonary endothelial cell barrier enhancement by sphingosine 1-phosphate: roles for cortactin and myosin light chain kinase", J BIOL CHEM., vol. 279, no. 23, 4 June 2004 (2004-06-04), pages 24692 - 700
WEED SA; PARSONS JT: "Cortactin: coupling membrane dynamics to cortical actin assembly", ONCOGENE, vol. 20, no. 44, 1 October 2001 (2001-10-01), pages 6418 - 34
SACHA E.: "Diabetic retinopathy. Current opinion on pathophysiology, diagnostics and therapy", PRZEGL LEK., vol. 62, no. 4, 2005, pages 238 - 42
FRANK RN.: "Diabetic retinopathy", N ENGL J MED., vol. 350, no. 1, 1 January 2004 (2004-01-01), pages 48 - 58
GARIANO RF; GARDNER TW.: "Retinal angiogenesis in development and disease", NATURE, vol. 438, no. 7070, 15 December 2005 (2005-12-15), pages 960 - 6
MURATA T; ISHIBASHI T; KHALIL A; HATA Y; YOSHIKAWA H; INOMATA H: "Vascular endothelial growth factor plays a role in hyperpermeability of diabetic retinal vessels", OPHTHALMIC RES., vol. 27, no. 1, 1995, pages 48 - 52
WEIS SM; CHERESH DA: "Pathophysiological consequences of VEGF-induced vascular permeability", NATURE, vol. 437, no. 7058, 22 September 2005 (2005-09-22), pages 497 - 504
KIEFER D; PANTUSO T.: "Panax ginseng", AM FAM PHYSICIAN, vol. 68, no. 8, 15 October 2003 (2003-10-15), pages 1539 - 42
LEE TK; JOHNKE RM; ALLISON RR; O'BRIEN KF; DOBBS U, JR.: "Radioprotective potential of ginseng", MUTAGENESIS, vol. 20, no. 4, July 2005 (2005-07-01), pages 237 - 43
KWON SW; HAN SB; PARK IH; KIM JM; PARK MK; PARK JH.: "Liquid chromatographic determination of less polar ginsenosides in processed ginseng", J CHROMATOGR A., vol. 921, no. 2, 6 July 2001 (2001-07-06), pages 335 - 9
KEUM YS; PARK KK; LEE JM ET AL.: "Antioxidant and anti-tumor promoting activities of the methanol extract of heat-processed ginseng", CANCER LETT., vol. 150, no. 1, 13 March 2000 (2000-03-13), pages 41 - 8
BROWNLEE M; CERAMI A; VLASSARA H: "Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications", N ENGL J MED., vol. 318, no. 20, 19 May 1988 (1988-05-19), pages 1315 - 21
BONNARDEL-PHU E; WAUTIER JL; SCHMIDT AM; AVILA C; VICAUT E: "Acute modulation of albumin microvascular leakageage by advanced glycation end products in microcirculation of diabetic rats in vivo", DIABETES, vol. 48, no. 10, October 1999 (1999-10-01), pages 2052 - 8
WOJCIAK-STOTHARD B; RIDLEY AJ: "Rho GTPases and the regulation of endothelial permeability", VASCUL PHARMACOL., vol. 39, no. 4-5, November 2002 (2002-11-01), pages 187 - 99
MIKI H; YAMAGUCHI H; SUETSUGU S; TAKENAWA T.: "IRSp53 is an essential intermediate between Rac and WAVE in the regulation of membrane ruffling", NATURE, vol. 408, no. 6813, 7 December 2000 (2000-12-07), pages 732 - 5
WU NZ; BALDWIN AL.: "Transient venular permeability increase and endothelial gap formation induced by histamine", AM J PHYSIOL., vol. 262, April 1992 (1992-04-01), pages H1238 - 47
EHRINGER WD; EDWARDS MJ; MILLER FN.: "Mechanisms of Alptha-thrombin, histamine, and bradykinin induced endothelial permeability", J CELL PHYSIOL., vol. 167, no. 3, June 1996 (1996-06-01), pages 562 - 9
WOJCIAK-STOTHARD B; POTEMPA S; EICHHOLTZ T; RIDLEY AJ.: "Rho and Rac but not Cdc42 regulate endothelial cell permeability", J CELL SCI., vol. 114, April 2001 (2001-04-01), pages 1343 - 55
YUN TK.: "Experimental and epidemiological evidence on non-organ specific cancer preventive effect of Korean ginseng and identification of active compounds", MUTAT RES., vol. 523-524, February 2003 (2003-02-01), pages 63 - 74
SENGUPTA S; TOH SA; SELLERS LA ET AL.: "Modulating angiogenesis: the yin and the yang in ginseng", CIRCULATION, vol. 110, no. 10, 7 September 2004 (2004-09-07), pages 1219 - 25
YUE PY; WONG DY; WU PK ET AL.: "The angiosuppressive effects of 20(R)- ginsenoside Rg3", BIOCHEM PHARMACOL., vol. 72, no. 4, 14 August 2006 (2006-08-14), pages 437 - 45
SATO K; MOCHIZUKI M; SAIKI I; YOO YC; SAMUKAWA K; AZUMA I.: "Inhibition of tumor angiogenesis and metastasis by a saponin of Panax ginseng, ginsenoside-Rb2", BIOL PHARM BULL., vol. 17, no. 5, May 1994 (1994-05-01), pages 635 - 9
LEUNG KW ET AL.: "Ginsenoside Rb1 inhibits tube-like structure formation of endothelial cells by regulating pigment epithelium-derived factor through the oestrogen beta receptor", BR J PHARMACOL., vol. 152, no. 2, September 2007 (2007-09-01), pages 207 - 15
MIN JK; KIM JH; CHO YL ET AL.: "20(S)-Ginsenoside Rg3 prevents endothelial cell apoptosis via inhibition of a mitochondrial caspase pathway", BIOCHEM BIOPHYS RES COMMUN., vol. 349, no. 3, 27 October 2006 (2006-10-27), pages 987 - 94
PAPAPETROPOULOS A.: "A ginseng-derived oestrogen receptor beta (ERbeta) agonist, Rbl ginsenoside, attenuates capillary morphogenesis", BR J PHARMACOL., vol. 152, no. 2, September 2007 (2007-09-01), pages 172 - 4
MICHEL CC; CURRY FE., PHYSIOL REV., vol. 79, no. 3, July 1999 (1999-07-01), pages 703 - 61
DUDEK SM; GARCIA JG.: "Cytoskeletal regulation of pulmonary vascular permeability", JAPPL PHYSIOL., vol. 91, no. 4, October 2001 (2001-10-01), pages 1487 - 500
GARCIA JG; SIFLINGER-BIRNBOIM A; BIZIOS R; DEL VECCHIO PJ; FENTON JW; MALIK AB.: "Thrombin-induced increase in albumin permeability across the endothelium", J CELL PHYSIOL., vol. 128, no. 1, July 1986 (1986-07-01), pages 96 - 104
LIU F; SCHAPHORST KL; VERIN AD ET AL.: "Hepatocyte growth factor enhances endothelial cell barrier function and cortical cytoskeletal rearrangement: potential role of glycogen synthase kinase-3beta", FASEB J., vol. 16, no. 9, July 2002 (2002-07-01), pages 950 - 62
ZENG L; XU H; CHEW TL ET AL.: "HMG CoA reductase inhibition modulates VEGF-induced endothelial cell hyperpermeability by preventing RhoA activation and myosin regulatory light chain phosphorylation", FASEBJ., vol. 19, no. 13, November 2005 (2005-11-01), pages 1845 - 7
See also references of EP 2495242A4
Attorney, Agent or Firm:
YANG, Boo-Hyun (1659-2 Inhundong Gwanak-gu, Seoul 151-832, KR)
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