title: Discovery of INT131: a selective PPARγ modulator that enhances insulin sensitivity.
abstract: PPARγ is a member of the nuclear hormone receptor family and plays a key role in the regulation of glucose homeostasis. This Letter describes the discovery of a novel chemical class of diarylsulfonamide partial agonists that act as selective PPARγ modulators (SPPARγMs) and display a unique pharmacological profile compared to the thiazolidinedione (TZD) class of PPARγ full agonists. Herein we report the initial discovery of partial agonist 4 and the structure-activity relationship studies that led to the selection of clinical compound INT131 (3), a potent PPARγ partial agonist that displays robust glucose-lowering activity in rodent models of diabetes while exhibiting a reduced side-effects profile compared to marketed TZDs.
authors.affiliation: Amgen, Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA. josh.taygerly@gmail.com
authors.forename: Joshua P
authors.initials: JP
authors.lastname: Taygerly
authors.forename: Lawrence R
authors.initials: LR
authors.lastname: McGee
authors.forename: Steven M
authors.initials: SM
authors.lastname: Rubenstein
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Houze
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Cushing
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.forename: Alykhan
authors.initials: A
authors.lastname: Motani
authors.forename: Jin-Long
authors.initials: JL
authors.lastname: Chen
authors.forename: Walter
authors.initials: W
authors.lastname: Frankmoelle
authors.forename: Guosen
authors.initials: G
authors.lastname: Ye
authors.forename: Marc R
authors.initials: MR
authors.lastname: Learned
authors.forename: Juan
authors.initials: J
authors.lastname: Jaen
authors.forename: Shichang
authors.initials: S
authors.lastname: Miao
authors.forename: Pieter B
authors.initials: PB
authors.lastname: Timmermans
authors.forename: Martin
authors.initials: M
authors.lastname: Thoolen
authors.forename: Patrick
authors.initials: P
authors.lastname: Kearney
authors.forename: John
authors.initials: J
authors.lastname: Flygare
authors.forename: Holger
authors.initials: H
authors.lastname: Beckmann
authors.forename: Jennifer
authors.initials: J
authors.lastname: Weiszmann
authors.forename: Michelle
authors.initials: M
authors.lastname: Lindstrom
authors.forename: Nigel
authors.initials: N
authors.lastname: Walker
authors.forename: Jinsong
authors.initials: J
authors.lastname: Liu
authors.forename: Donna
authors.initials: D
authors.lastname: Biermann
authors.forename: Zhulun
authors.initials: Z
authors.lastname: Wang
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hagiwara
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Iida
authors.forename: Hisateru
authors.initials: H
authors.lastname: Aramaki
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kitao
authors.forename: Hisashi
authors.initials: H
authors.lastname: Shinkai
authors.forename: Noboru
authors.initials: N
authors.lastname: Furukawa
authors.forename: Jun
authors.initials: J
authors.lastname: Nishiu
authors.forename: Motonao
authors.initials: M
authors.lastname: Nakamura
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D006207:Half-Life; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011804:Quinolines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; C541917:INT 131; D047495:PPAR gamma; D011804:Quinolines; D013449:Sulfonamides; D003577:Cytochrome P-450 Enzyme System; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A