Potent and selective protein tyrosine phosphatase 1b inhibitors

MEDI 425

Zhao-Kui Wan1, Jinbo Lee1, Douglas Wilson1, Dave Erbe2, Weixin Xu3, Yan-Ling Zhang4, Lori Klaman4, Diane Joseph-McCarthy5, Xin Xu, xxu@wyeth.com6, Bruce Follows, bfollows@wyeth.com1, Junjun Wu1, Steven Kirincich5, Alessandro F. Moretto, amoretto@wyeth.com5, Eva Binnun1, Rajeev Hotchandani, rhotchandani@wyeth.com5, Manus Ipek, mipek@wyeth.com1, May Tam2, Sarah Will7, Ariful Qadri7, James Tobin7, and Steve Tam5. (1) Chemical and Screening Sciences, Wyeth Research, 200 Cambridgepark Drive, Cambridge, MA 02140, (2) Cardiovascular and Metabolic Disease, Wyeth Research, 200 Cambridge Park Drive, Cambridge, MA 02140, (3) Structural Biology, Wyeth Research, Cambridge, MA 02140, (4) Cardiovascular and Metabolic Diseases, Wyeth, 200 Cambridge Park Drive, Cambridge, MA 02140, (5) Chemical and Screening Sciences, Wyeth, 200 Cambridge Park Drive, Cambridge, MA 02140, (6) Department of Drug Safety and Metabolism, Wyeth Research, One Burtt Road, Andover, MA 01810, (7) Cardiovascular & Metabolic Disease, Wyeth Research, 200 CambridgePark Drive, Cambridge, 02140
Diabetes mellitus is among the most serious metabolic diseases. Protein tyrosine phosphatase 1b (PTP1b) has been shown to negatively regulate both insulin and leptin pathways. PTP1b knockout mice exhibited decrease insulin levels, improved insulin sensitivity, and resistance to weight gain on high-fat diet, without any significant negative side effects. Therefore, inhibition of PTP1b could augment the action of both insulin and leptin signaling. PTP1b is thus considered to be a promising therapeutic target for both type 2 diabetes and obesity. Novel thiophenes were discovered as potent PTP1b inhibitors. Great success has been achieved both by capturing an interaction with Asp48/Arg47 and extending inhibitors into a secondary phosphotyrosine-binding site. Many single digit nM inhibitors were developed. This presentation will highlight efforts in discovering and optimizing potent and selective PTP1b inhibitors, as guided by structural information and molecular modeling. In vivo efficacy with a prodrug of one of these potent inhibitors in ob/ob mice will also be discussed.
 

General Poster Session
7:00 PM-9:00 PM, Wednesday, 13 September 2006 Moscone Center -- Hall D, Poster

Division of Medicinal Chemistry

The 232nd ACS National Meeting, San Francisco, CA, September 10-14, 2006