title: Discovery of XL335 (WAY-362450), a highly potent, selective, and orally active agonist of the farnesoid X receptor (FXR).
abstract: Azepino[4,5-b]indoles have been identified as potent agonists of the farnesoid X receptor (FXR). In vitro and in vivo optimization has led to the discovery of 6m (XL335, WAY-362450) as a potent, selective, and orally bioavailable FXR agonist (EC(50) = 4 nM, Eff = 149%). Oral administration of 6m to LDLR(-/-) mice results in lowering of cholesterol and triglycerides. Chronic administration in an atherosclerosis model results in significant reduction in aortic arch lesions.
authors.affiliation: Department of Medicinal Chemistry, Exelixis Inc., 4757 Nexus Centre Drive, San Diego, California 92121, USA. bflatt@exelixis.com
authors.forename: Brenton
authors.initials: B
authors.lastname: Flatt
authors.forename: Richard
authors.initials: R
authors.lastname: Martin
authors.forename: Tie-Lin
authors.initials: TL
authors.lastname: Wang
authors.forename: Paige
authors.initials: P
authors.lastname: Mahaney
authors.forename: Brett
authors.initials: B
authors.lastname: Murphy
authors.forename: Xiao-Hui
authors.initials: XH
authors.lastname: Gu
authors.forename: Paul
authors.initials: P
authors.lastname: Foster
authors.forename: Jiali
authors.initials: J
authors.lastname: Li
authors.forename: Parinaz
authors.initials: P
authors.lastname: Pircher
authors.forename: Mary
authors.initials: M
authors.lastname: Petrowski
authors.forename: Ira
authors.initials: I
authors.lastname: Schulman
authors.forename: Stefan
authors.initials: S
authors.lastname: Westin
authors.forename: Jay
authors.initials: J
authors.lastname: Wrobel
authors.forename: Grace
authors.initials: G
authors.lastname: Yan
authors.forename: Eric
authors.initials: E
authors.lastname: Bischoff
authors.forename: Chris
authors.initials: C
authors.lastname: Daige
authors.forename: Raju
authors.initials: R
authors.lastname: Mohan
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001013:Aorta, Thoracic / Q000473:pathology; D050197:Atherosclerosis / Q000188:drug therapy* / Q000517:prevention & control; D001381:Azepines / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D002784:Cholesterol / Q000097:blood; D004268:DNA-Binding Proteins / Q000819:agonists*; D004195:Disease Models, Animal; D055808:Drug Discovery; D007211:Indoles / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D018345:Mice, Knockout; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D011973:Receptors, LDL / Q000172:deficiency; D014157:Transcription Factors / Q000819:agonists*; D014280:Triglycerides / Q000097:blood; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001381:Azepines; D002784:Cholesterol; D004268:DNA-Binding Proteins; D007211:Indoles; D018160:Receptors, Cytoplasmic and Nuclear; D011973:Receptors, LDL; D014157:Transcription Factors; D014280:Triglycerides; D000099150:Receptor, Farnesoid X-Activated; C540004:WAY-362450