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

• Published in: ACS medicinal chemistry letters Vol. 4; no. 4; pp. 414 - 418
• Main Authors: Qian, Yimin, Corbett, Wendy L, Berthel, Steven J, Choi, Duk Soon, Dvorozniak, Mark T, Geng, Wanping, Gillespie, Paul, Guertin, Kevin R, Haynes, Nancy-Ellen, Kester, Robert F, Mennona, Francis A, Moore, David, Racha, Jagdish, Radinov, Roumen, Sarabu, Ramakanth, Scott, Nathan R, Grimsby, Joseph, Mallalieu, Navita L
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 11-04-2013
• Subjects: Letter; lipophilic ligand efficiency; redox cycling; type 2 diabetes; metabolite; Glucokinase activator
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/ml400027y

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.