Discovery of 6-(4-{[5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl]methoxy}piperidin-1-yl)-1-methyl-1H-indole-3-carboxylic Acid: A Novel FXR Agonist for the Treatment of Dyslipidemia

Journal of Medicinal Chemistry

Volumn 58, Issue 24, 2015, Pages 9768-9772

  Genin, Michael J ^a   Bueno, Ana B ^a   Agejas Francisco, Javier ^a   Manninen, Peter R ^a   Bocchinfuso, Wayne P ^a   Montrose Rafizadeh, Chahrzad ^a   Cannady, Ellen A ^a   Jones, Timothy M ^a   Stille, John R ^a   Raddad, Eyas ^a   Reidy, Charles ^a   Cox, Amy ^a   Michael, M Dodson ^a   Michael, Laura F ^a  

^a ELI LILLY AND COMPANY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CARBOXYLIC ACID DERIVATIVE; FARNESOID X RECEPTOR; HIGH DENSITY LIPOPROTEIN; HORMONE RECEPTOR STIMULATING AGENT; LOW DENSITY LIPOPROTEIN; LOW DENSITY LIPOPROTEIN RECEPTOR; PLACEBO; UNCLASSIFIED DRUG; VERY LOW DENSITY LIPOPROTEIN; [4 [[5 CYCLOPROPYL 3 (2,6 DICHLOROPHENYL)ISOXAZOL 4 YL]METHOXY]PIPERIDIN 1 YK] 1 METHYL 1H INDOLE 3 CARBOXYLIC ACID; 6-(4-((5-CYCLOPROPYL-3-(2,6-DICHLOROPHENYL)ISOXAZOL-4-YL)METHOXY)PIPERIDIN-1-YL)-1-METHYL-1H-INDOLE-3-CARBOXYLIC ACID; ANTILIPEMIC AGENT; CELL RECEPTOR; CHOLESTEROL; FARNESOID X-ACTIVATED RECEPTOR; INDOLE DERIVATIVE; ISOXAZOLE DERIVATIVE; TRIACYLGLYCEROL;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; ATHEROSCLEROSIS; BROMINATION; CONTROLLED STUDY; CYCLIZATION; DOSE RESPONSE; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG DOSE INCREASE; DRUG EFFICACY; DRUG POTENCY; DRUG SYNTHESIS; DYSLIPIDEMIA; ELIMINATION HALF-LIFE; HEK293 CELL LINE; IN VITRO STUDY; IN VIVO STUDY; LIPID BLOOD LEVEL; MALE; MAXIMUM PLASMA CONCENTRATION; MOUSE; NONHUMAN; SINGLE DRUG DOSE; TIME TO MAXIMUM PLASMA CONCENTRATION; TRANSCRIPTION INITIATION; TREATMENT DURATION; AGONISTS; ANIMAL; BLOOD; CHEMISTRY; CLINICAL TRIAL; DOG; DOUBLE BLIND PROCEDURE; DYSLIPIDEMIAS; FEMALE; GENETICS; HUMAN; KNOCKOUT MOUSE; MACACA FASCICULARIS; RAT; SPRAGUE DAWLEY RAT; STRUCTURE ACTIVITY RELATION;

ANIMALS; CHOLESTEROL; DOGS; DOUBLE-BLIND METHOD; DYSLIPIDEMIAS; FEMALE; HEK293 CELLS; HUMANS; HYPOLIPIDEMIC AGENTS; INDOLES; ISOXAZOLES; MACACA FASCICULARIS; MALE; MICE; MICE, KNOCKOUT; RATS; RATS, SPRAGUE-DAWLEY; RECEPTORS, CYTOPLASMIC AND NUCLEAR; RECEPTORS, LDL; STRUCTURE-ACTIVITY RELATIONSHIP; TRIGLYCERIDES;

EID: 84953340917     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/acs.jmedchem.5b01161     Document Type: Article

References (8)

1. Wang, H.; Chen, J.; Hollister, K.; Sowers, L. C.; Forman, B. M. Endogenous bile acids are ligands for the nuclear receptor FXR/BAR Mol. Cell 1999, 3, 543-53 10.1016/S1097-2765(00)80348-2
2. Parks, D. J.; Blanchard, S. G.; Bledsoe, R. K.; Chandra, G.; Consler, T. G.; Kliewer, S. A.; Stimmel, J. B.; Willson, T. M.; Zavacki, A. M.; Moore, D. D.; Lehmann, J. M. Bile acids: natural ligands for an orphan nuclear receptor Science 1999, 284, 1365-1368 10.1126/science.284.5418.1365
3. Makishima, M.; Okamoto, A. Y.; Repa, J. J.; Tu, H.; Learned, R. M.; Luk, A.; Hull, M. V.; Lustig, K. D.; Mangelsdorf, D. J.; Shan, B. Identification of a nuclear receptor for bile acids Science 1999, 284, 1362-1365 10.1126/science.284.5418.1362
4. Lambert, G.; Amar, M. J.; Guo, G.; Brewer, H. B., Jr.; Gonzalez, F. J.; Sinal, C. J. The farnesoid X-receptor is an essential regulator of cholesterol homeostasis J. Biol. Chem. 2003, 278, 2563-70 10.1074/jbc.M209525200
5. Goodwin, B.; Jones, S. A.; Price, R. R.; Watson, M. A.; McKee, D. D.; Moore, L. B.; Galardi, C.; Wilson, J. G.; Lewis, M. C.; Roth, M. E.; Maloney, P. R.; Willson, T. M.; Kliewer, S. A. Mol. Cell 2000, 6, 517-526 10.1016/S1097-2765(00)00051-4
6. Hanniman, E. A.; Lambert, G.; McCarthy, T. C.; Sinal, C. J. Loss of functional farnesoid X receptor increases atherosclerotic lesions in apolipoprotein E-deficient mice J. Lipid Res. 2005, 46, 2595-604 10.1194/jlr.M500390-JLR200
7. Henneman, P.; Schaap, F. G.; Havekes, L. M.; Rensen, P. C.; Frants, R. R.; van Tol, A.; Hattori, H.; Smelt, A. H.; van Dijk, K. W. Plasma apoAV levels are markedly elevated in severe hypertriglyceridemia and positively correlated with the APOA5 S19W polymorphism Atherosclerosis 2007, 193, 129-34 10.1016/j.atherosclerosis.2006.05.030
8. Davies, B.; Morris, T. Physiological parameters in laboratory animals and humans Pharm. Res. 1993, 10, 1095-93 10.1023/A:1018943613122