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

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• 作者：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
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2013
• 出版时间：April 11, 2013
• 年：2013
• 卷：4
• 期：4
• 页码：414-418
• 全文大小：318K
• 年卷期：v.4,no.4(April 11, 2013)
• ISSN：1948-5875

文摘

To resolve the metabolite redox cycling associated with our earlier clinical compound <b>2b>, we carried out lead optimization of lead molecule <b>1b>. Compound <b>4b> 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.<br>

Keywords:

Glucokinase activator; type 2 diabetes; lipophilic ligand efficiency; metabolite; redox cycling