Synthesis, SAR, and in vivo efficacy of novel GPR119 agonists with a 4-[3-(4-methanesulfinylphenoxy)propyl]-1-Boc-piperidine core

MEDI 62

Matthew C. T. Fyfe, mfyfe@prosidion.com, Adam J. Babbs, Lisa S. Bertram, Stuart E. Bradley, Sheila M. Doel, Smita Gadher, William T. Gattrell, Revathy P. Jeevaratnam, John F. Keily, James G. McCormack, Hilary A. Overton, Chrystelle M. Rasamison, Christine Reynet, Philip J. Rushworth, Colin P. Sambrook Smith, Vilas K. Shah, David F. Stonehouse, Simon A. Swain, Jonathan R. White, Peter S. Widdowson, Geoffrey M. Williams, and Martin J. Procter. Prosidion Limited, Windrush Court, Watlington Road, Oxford, OX4 6LT, United Kingdom
GPR119 is a Gas-coupled class A GPCR expressed predominantly in the pancreas and gastrointestinal tract. Agonists of this receptor could represent a rare opportunity for oral agents to achieve blood glucose control with simultaneous body weight loss, an outcome only possible with injectable therapeutics at present. Here, we describe the optimization of the previously-described pyridine-containing GPR119 agonist PSN632408, utilizing a yeast-based fluorimetric assay, which led to the discovery of the more potent sulfoxide PSN119-1. When administered orally to rats, this compound achieved high plasma concentrations, as did its active sulfone metabolite PSN119-1M. In several rodent models of obesity and type 2 diabetes, PSN119-1 reduced food intake and improved oral glucose tolerance, giving credence to the premise that GPR119 agonists have the makings of effective oral antidiabesic agents.

 

Poster Session
7:00 PM-9:00 PM, Sunday, August 19, 2007 BCEC -- Exhibit Hall - B2, Poster

Division of Medicinal Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007