title: 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.
abstract: The farnesoid X receptor (FXR) is a member of the "metabolic" subfamily of nuclear receptors. Several FXR agonists have been reported in the literature to have profound effects on plasma lipids in animal models. To discover novel and effective therapies for dyslipidemia and atherosclerosis, we have developed a series of potent FXR agonists that robustly lower plasma LDL and vLDL in LDLr-/- mice. To this end the novel piperidinylisoxazole system LY2562175 was discovered. This molecule is a potent and selective FXR agonist in vitro and has robust lipid modulating properties, lowering LDL and triglycerides while raising HDL in preclinical species. The preclinical ADME properties of LY2562175 were consistent with enabling once daily dosing in humans, and it was ultimately advanced to the clinic for evaluation in humans. The synthesis and biological profile of this molecule is discussed.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Genin
authors.forename: Ana B
authors.initials: AB
authors.lastname: Bueno
authors.forename: Javier
authors.initials: J
authors.lastname: Agejas Francisco
authors.forename: Peter R
authors.initials: PR
authors.lastname: Manninen
authors.forename: Wayne P
authors.initials: WP
authors.lastname: Bocchinfuso
authors.forename: Chahrzad
authors.initials: C
authors.lastname: Montrose-Rafizadeh
authors.forename: Ellen A
authors.initials: EA
authors.lastname: Cannady
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Jones
authors.affiliation: Chorus, Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
authors.forename: John R
authors.initials: JR
authors.lastname: Stille
authors.affiliation: Chorus, Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
authors.forename: Eyas
authors.initials: E
authors.lastname: Raddad
authors.forename: Charles
authors.initials: C
authors.lastname: Reidy
authors.forename: Amy
authors.initials: A
authors.lastname: Cox
authors.forename: M Dodson
authors.initials: MD
authors.lastname: Michael
authors.forename: Laura F
authors.initials: LF
authors.lastname: Michael
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000097:blood; D004285:Dogs; D004311:Double-Blind Method; D050171:Dyslipidemias / Q000188:drug therapy*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D000960:Hypolipidemic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D007211:Indoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D007555:Isoxazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D011973:Receptors, LDL / Q000235:genetics; D013329:Structure-Activity Relationship; D014280:Triglycerides / Q000097:blood; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D002784:Cholesterol; D000960:Hypolipidemic Agents; D007211:Indoles; D007555:Isoxazoles; D018160:Receptors, Cytoplasmic and Nuclear; D011973:Receptors, LDL; D014280:Triglycerides; D000099150:Receptor, Farnesoid X-Activated; C000607197:6-(4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)piperidin-1-yl)-1-methyl-1H-indole-3-carboxylic acid