title: INT131: a selective modulator of PPAR gamma.
abstract: The nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPAR gamma; NR1C3) plays a central role in adipogenesis and is the molecular target of the thiazolidinedione class of antidiabetic drugs. To overcome the well-known shortcomings of thiazolidinediones, we have identified INT131 (formerly T131 and AMG131) as a potent selective ligand for PPAR gamma that is structurally and pharmacologically distinct from glitazone agonists. In vitro biochemical and cell-based functional assays showed that INT131 mediates a distinct pattern of coregulator recruitment to PPAR gamma. In adipocytes, INT131 showed minimal stimulation of adipocyte differentiation and partially activated PPAR gamma target genes involved in adipogenesis and, at the same time, showed more agonistic activity on another set of target genes that may influence insulin sensitivity directly. These unique properties of INT131 may provide a mechanistic basis for its distinct pharmacological profile. In vivo, increases in glucose tolerance were observed in Zucker (fa/fa) rats following a 14-day oral treatment with INT131. Although the maximal efficacies of INT131 and rosiglitazone were similar with respect to improvements in glucose tolerance, INT131 had less effect on heart and lung weights, weight gain, hemodilution, and plasma volume. Thus, INT131 appears to selectively modulate PPAR gamma responses in an in vivo preclinical model, showing antidiabetic efficacy while exhibiting an improved hemodynamic and cardiovascular adverse effect profile compared to the full agonist rosiglitazone. X-ray crystallography revealed that INT131 interacts with PPAR gamma through a distinct binding mode, forming primarily hydrophobic contacts with the ligand-binding pocket without direct hydrogen-bonding interactions to key residues in helix 12 that are characteristic of full agonists. Mutagenesis studies on Tyr473 in helix 12 demonstrated this residue as essential for rosiglitazone-induced receptor activation, but nonessential for INT131 function in vitro, providing one possible molecular determinant for INT131's distinct pharmacology. INT131 is currently being evaluated in a clinical setting as a therapeutic agent for the treatment of type 2 diabetes.
authors.affiliation: Amgen, Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Alykhan
authors.initials: A
authors.lastname: Motani
authors.forename: Zhulun
authors.initials: Z
authors.lastname: Wang
authors.forename: Jennifer
authors.initials: J
authors.lastname: Weiszmann
authors.forename: Lawrence R
authors.initials: LR
authors.lastname: McGee
authors.forename: Gary
authors.initials: G
authors.lastname: Lee
authors.forename: Qingxiang
authors.initials: Q
authors.lastname: Liu
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Staunton
authors.forename: Zexu
authors.initials: Z
authors.lastname: Fang
authors.forename: Helen
authors.initials: H
authors.lastname: Fuentes
authors.forename: Michelle
authors.initials: M
authors.lastname: Lindstrom
authors.forename: Jinsong
authors.initials: J
authors.lastname: Liu
authors.forename: Donna H T
authors.initials: DH
authors.lastname: Biermann
authors.forename: Juan
authors.initials: J
authors.lastname: Jaen
authors.forename: Nigel P C
authors.initials: NP
authors.lastname: Walker
authors.forename: R Marc
authors.initials: RM
authors.lastname: Learned
authors.forename: Jin-Long
authors.initials: JL
authors.lastname: Chen
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D054333:Drug Partial Agonism; D057927:Hydrophobic and Hydrophilic Interactions; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D051379:Mice; D008969:Molecular Sequence Data; D047495:PPAR gamma / Q000819:agonists* / Q000737:chemistry; D011485:Protein Binding; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011924:Rats, Zucker; D000077154:Rosiglitazone; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D045162:Thiazolidinediones / Q000737:chemistry / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; C541917:INT 131; D007328:Insulin; D047495:PPAR gamma; D011804:Quinolines; D013449:Sulfonamides; D045162:Thiazolidinediones; D000077154:Rosiglitazone