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PPAR Research
Volume 2008, Article ID 936906, 9 pages
http://dx.doi.org/10.1155/2008/936906
Review Article

The Development of INT131 as a Selective PPAR 𝜸 Modulator: Approach to a Safer Insulin Sensitizer

1InteKrin Therapeutics, Inc., 4300 El Camino Real, Suite 201, Los Altos, CA 94022, USA
2Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA

Received 18 March 2008; Accepted 14 June 2008

Academic Editor: Anne Miller

Copyright © 2008 Linda S. Higgins and Christos S. Mantzoros. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

INT131 (formerly T0903131, T131, AMG131) is a potent non-thiazolidinedione (TZD) selective peroxisome proliferator-activated receptor 𝛾 modulator (SPPARM) currently in Phase 2 clinical trials for treatment of type-2 diabetes mellitus (T2DM). This new chemical entity represents a second generation SPPARM approach developed after the first generation PPAR 𝛾 full agonists to address their inherent limitations. INT131 was specifically and carefully designed using preclinical models to exhibit a biological profile of strong efficacy with de minimis side effects compared to PPAR 𝛾 full agonists. As a potent PPAR 𝛾 modulator, INT131 binds to PPAR 𝛾 with high affinity. In pharmacology models of diabetes and in early clinical studies, it achieved a high level of efficacy in terms of antidiabetic actions such as insulin sensitization and glucose and insulin lowering, but had little activity in terms of other, undesired, effects associated with TZD PPAR 𝛾 full agonists such as edema and adipogenesis. Ongoing clinical development is directed at translating these findings into establishing a novel and effective treatment for T2DM patients with an improved safety profile in relation to that currently available.