the development of int131 as a selective ppar modulator approach to a safer insulin sensitizerint131的发展作为选择性ppar调制器的方法更安全的胰岛素敏化剂.pdfVIP

Hindawi Publishing Corporation PPAR Research Volume 2008, Article ID 936906, 9 pages doi:10.1155/2008/936906 Review Article The Development of INT131 as a Selective PPARγ Modulator: Approach to a Safer Insulin Sensitizer Linda S. Higgins1 and Christos S. Mantzoros2 1 InteKrin Therapeutics, Inc., 4300 El Camino Real, Suite 201, Los Altos, CA 94022, USA 2 Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA Correspondence should be addressed to Linda S. Higgins, linda@ Received 18 March 2008; Accepted 14 June 2008 Recommended by Anne Miller 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 PPARγ 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 PPARγ full agonists. As a potent PPARγ modulator, INT131 binds to PPARγ 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 PPARγ 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