Title:
PYRIPYROPENE DERIVATIVE HAVING ACAT2-INHIBITING ACTIVITY
Document Type and Number:
WIPO Patent Application WO/2009/081957
Kind Code:
A1
Abstract:
Disclosed are: a compound represented by the general formula (I), (II) or (III), or a pharmacologically acceptable salt, solvate or hydrate thereof; and a pharmaceutical composition comprising the compound or the pharmacologically acceptable salt, solvate or hydrate thereof as an active ingredient. The compound has an excellent ACAT2-inhibiting activity, and the mechanism of action of the compound is different from that of a statin-containing pharmaceutical agent. Therefore, the compound can be used as a therapeutic or prophylactic agent for obesity; adiposis; hyperlipemia; hypercholesterolemia; metabolic dyslipidemia; arteriosclerosis; hyperlipemia, hypercholesterolemia, metabolic dyslipidemia, arteriosclerosis or hypertension induced by obesity; or the like.
Inventors:
TOMODA HIROSHI (JP)
NAGAMITSU TOHRU (JP)
OMURA SATOSHI (JP)
LAWRENCE LEE RUDEL (US)
NAGAMITSU TOHRU (JP)
OMURA SATOSHI (JP)
LAWRENCE LEE RUDEL (US)
Application Number:
PCT/JP2008/073501
Publication Date:
July 02, 2009
Filing Date:
December 17, 2008
Export Citation:
Assignee:
KITASATO INST (JP)
TOMODA HIROSHI (JP)
NAGAMITSU TOHRU (JP)
OMURA SATOSHI (JP)
LAWRENCE LEE RUDEL (US)
TOMODA HIROSHI (JP)
NAGAMITSU TOHRU (JP)
OMURA SATOSHI (JP)
LAWRENCE LEE RUDEL (US)
International Classes:
C07D493/04; A61K31/4433; A61K31/695; A61P9/10; A61P43/00; C07D493/14; C07F7/18
Domestic Patent References:
| WO2006129714A1 | 2006-12-07 |
Foreign References:
| JPH08259569A | 1996-10-08 | |||
| JPH08269065A | 1996-10-15 |
Other References:
THE PHARMACEUTICAL SOCIETY OF JAPAN NENKAI YOSHISHU, vol. 127, no. 4, 5 March 2007 (2007-03-05), pages 6
THE PHARMACEUTICAL SOCIETY OF JAPAN NENKAI YOSHISHU, vol. 126, no. 3, 6 March 2006 (2006-03-06), pages 21
OHSHIRO, T. ET AL.: "Selectivity of microbial acyl -CoA: cholesterol acyltransferase inhibitors toward isozymes", JOURNAL OF ANTIBIOTICS, vol. 60, no. 1, 2007, pages 43 - 51, XP008137566
CHO, K. ET AL.: "Mass-production of human ACAT-1 and ACAT-2 to screen isoform-specific inhibitor: a different substrate specificity and inhibitory regulation", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 309, no. 4, 2003, pages 864 - 872, XP004455821
LADA, A.T. ET AL.: "Identification of ACAT1- and ACAT2-specific inhibitors using a novel, cell- based fluorescence assay: Individual ACAT uniqueness", JOURNAL OF LIPID RESEARCH, vol. 45, no. 2, 2004, pages 378 - 386, XP008137572
OBATA, R. ET AL.: "Structure-activity relationships study of pyripyropenes: reversal of cancer cell multidrug resistance", JOURNAL OF ANTIBIOTICS, vol. 53, no. 4, 2000, pages 422 - 425, XP008137617
OBATA, R. ET AL.: "Chemical modification and structure-activity relationships of pyripyropenes. 3. Synthetic conversion of pyridine-pyrone moiety", JOURNAL OF ANTIBIOTICS, vol. 50, no. 3, 1997, pages 229 - 236, XP008137574
OBATA, R. ET AL.: "Chemical modification and structure-activity relationships of pyripyropenes. 2. 1, 11-Cyclic analogs", JOURNAL OF ANTIBIOTICS, vol. 49, no. 11, 1996, pages 1149 - 1156, XP008130150
OBATA, R. ET AL.: "Chemical modification and structure-activity relationships of pyripyropenes. 1. Modification at the four hydroxyl groups", JOURNAL OF ANTIBIOTICS, vol. 49, no. 11, 1996, pages 1133 - 1148, XP003002774
TOMODA, H. ET AL.: "Pyripyropenes, novel ACAT inhibitors produced by Aspergillus fumigatus IV. Structure elucidation of pyripyropenes M to R", JOURNAL OF ANTIBIOTICS, vol. 49, no. 3, 1996, pages 292 - 298, XP008137616
OBATA, R. ET AL.: "Structure-activity relationships of pyripyropenes fungal acyl-CoA: cholesterol acyltransferase inhibitors", JOURNAL OF ANTIBIOTICS, vol. 48, no. 7, 1995, pages 749 - 750, XP008137618
OBATA, R. ET AL.: "Chemical modification and structure-activity relationships of pyripyropenes; potent, bioavailable inhibitor of acyl-CoA: cholesterol O-acyltransferase (ACAT)", BIOORGANIC, XP004135214
TAMIO TERAMOTO; NAKAYAMA SHOTEN, LIFESTYLE RELATED DISEASE, 2001, pages 119
MEUWESE ET AL., CURR. OPIN. LIPIDOL., vol. 17, 2006, pages 426 - 431
CHANG ET AL., ACTA. BIOCHIM. BIOPHYS. SIN., vol. 38, 2006, pages 151 - 156
FARESE, ARTERIOSCLER. THROMB. VASC. BIOL., vol. 26, 2006, pages 1684 - 1686
BELL ET AL., ARTERIOSCLER. THROMB. VASC. BIOL., vol. 27, 2007, pages 1396 - 1402
TOMODA ET AL., J. ANTIBIOT., vol. 47, 1994, pages 148 - 153
LADA ET AL., J. LIPID RES., vol. 45, 2004, pages 378 - 386
OBATA ET AL., J. ANTIBIOT., vol. 49, 1996, pages 1133 - 1148
OBATA ET AL., J. ANTIBIOT., vol. 49, 1996, pages 1149 - 1156
UELMEN ET AL., J. BIOL. CHEM, vol. 270, 1995, pages 26192 - 26201
BLIGH; DYER, CAN. J. BIOCHEM. PHYSIOL., vol. 37, 1959, pages 911 - 917
THE PHARMACEUTICAL SOCIETY OF JAPAN NENKAI YOSHISHU, vol. 126, no. 3, 6 March 2006 (2006-03-06), pages 21
OHSHIRO, T. ET AL.: "Selectivity of microbial acyl -CoA: cholesterol acyltransferase inhibitors toward isozymes", JOURNAL OF ANTIBIOTICS, vol. 60, no. 1, 2007, pages 43 - 51, XP008137566
CHO, K. ET AL.: "Mass-production of human ACAT-1 and ACAT-2 to screen isoform-specific inhibitor: a different substrate specificity and inhibitory regulation", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 309, no. 4, 2003, pages 864 - 872, XP004455821
LADA, A.T. ET AL.: "Identification of ACAT1- and ACAT2-specific inhibitors using a novel, cell- based fluorescence assay: Individual ACAT uniqueness", JOURNAL OF LIPID RESEARCH, vol. 45, no. 2, 2004, pages 378 - 386, XP008137572
OBATA, R. ET AL.: "Structure-activity relationships study of pyripyropenes: reversal of cancer cell multidrug resistance", JOURNAL OF ANTIBIOTICS, vol. 53, no. 4, 2000, pages 422 - 425, XP008137617
OBATA, R. ET AL.: "Chemical modification and structure-activity relationships of pyripyropenes. 3. Synthetic conversion of pyridine-pyrone moiety", JOURNAL OF ANTIBIOTICS, vol. 50, no. 3, 1997, pages 229 - 236, XP008137574
OBATA, R. ET AL.: "Chemical modification and structure-activity relationships of pyripyropenes. 2. 1, 11-Cyclic analogs", JOURNAL OF ANTIBIOTICS, vol. 49, no. 11, 1996, pages 1149 - 1156, XP008130150
OBATA, R. ET AL.: "Chemical modification and structure-activity relationships of pyripyropenes. 1. Modification at the four hydroxyl groups", JOURNAL OF ANTIBIOTICS, vol. 49, no. 11, 1996, pages 1133 - 1148, XP003002774
TOMODA, H. ET AL.: "Pyripyropenes, novel ACAT inhibitors produced by Aspergillus fumigatus IV. Structure elucidation of pyripyropenes M to R", JOURNAL OF ANTIBIOTICS, vol. 49, no. 3, 1996, pages 292 - 298, XP008137616
OBATA, R. ET AL.: "Structure-activity relationships of pyripyropenes fungal acyl-CoA: cholesterol acyltransferase inhibitors", JOURNAL OF ANTIBIOTICS, vol. 48, no. 7, 1995, pages 749 - 750, XP008137618
OBATA, R. ET AL.: "Chemical modification and structure-activity relationships of pyripyropenes; potent, bioavailable inhibitor of acyl-CoA: cholesterol O-acyltransferase (ACAT)", BIOORGANIC, XP004135214
TAMIO TERAMOTO; NAKAYAMA SHOTEN, LIFESTYLE RELATED DISEASE, 2001, pages 119
MEUWESE ET AL., CURR. OPIN. LIPIDOL., vol. 17, 2006, pages 426 - 431
CHANG ET AL., ACTA. BIOCHIM. BIOPHYS. SIN., vol. 38, 2006, pages 151 - 156
FARESE, ARTERIOSCLER. THROMB. VASC. BIOL., vol. 26, 2006, pages 1684 - 1686
BELL ET AL., ARTERIOSCLER. THROMB. VASC. BIOL., vol. 27, 2007, pages 1396 - 1402
TOMODA ET AL., J. ANTIBIOT., vol. 47, 1994, pages 148 - 153
LADA ET AL., J. LIPID RES., vol. 45, 2004, pages 378 - 386
OBATA ET AL., J. ANTIBIOT., vol. 49, 1996, pages 1133 - 1148
OBATA ET AL., J. ANTIBIOT., vol. 49, 1996, pages 1149 - 1156
UELMEN ET AL., J. BIOL. CHEM, vol. 270, 1995, pages 26192 - 26201
BLIGH; DYER, CAN. J. BIOCHEM. PHYSIOL., vol. 37, 1959, pages 911 - 917
Attorney, Agent or Firm:
KOBAYASHI, Kazunori (25-1 Kitaotsuka 2-chom, Toshima-ku Tokyo 04, JP)
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