Identification of RO4597014, a Glucokinase Activator Studied in the Clinic for the Treatment of Type 2 Diabetes.

Abstract

To resolve the metabolite redox cycling associated with our earlier clinical compound 2, we carried out lead optimization of lead molecule 1. Compound 4 showed improved lipophilic ligand efficiency and demonstrated robust glucose lowering in diet-induced obese mice without a liability in predictive preclinical drug safety studies. Thus, it was selected as a clinical candidate and further studied in type 2 diabetic patients. Clinical data suggests no evidence of metabolite cycling, which is consistent with the preclinical profiling of metabolism.

• Authors: Yimin Qian, Wendy L Corbett, Steven J Berthel, Duk Soon Choi, Mark T Dvorozniak, Wanping Geng, Paul Gillespie, Kevin R Guertin, Nancy-Ellen Haynes, Robert F Kester, Francis A Mennona, David Moore, Jagdish Racha, Roumen Radinov, Ramakanth Sarabu, Nathan R Scott, Joseph Grimsby, Navita L Mallalieu
• Journal: ACS medicinal chemistry letters (ACS Med Chem Lett) Vol. 4 Issue 4 Pg. 414-8 (Apr 11 2013) ISSN: 1948-5875 [Print] United States
• PMID: 24900686 (Publication Type: Journal Article)