Benzimidazole-carboxamides as potent and bioavailable stearoyl-CoA desaturase (SCD1) inhibitors from ligand-based virtual screening and chemical optimization

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• 作者：Hans Matter^a ; ^{Hans.Matter@sanofi.com} ; Gerhard Zoller^a ; Andreas W. Herling^a ; Juan-Antonio Sanchez-Arias^b ; ^&dagger ; ; Christophe Philippo^c ; Claudie Namane^c ; Markus Kohlmann^a ; Anja Pfenninger^a ; Marc D. Voss^a
• 关键词：Benzimidazole ; SCD1 ; SCD1 inhibition ; Diabetes ; Enzyme inhibition ; Virtual screening
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2013
• 出版时间：15 March, 2013
• 年：2013
• 卷：23
• 期：6
• 页码：1817-1822
• 全文大小：3491 K

文摘

The discovery of potent benzimidazole stearoyl-CoA desaturase (SCD1) inhibitors by ligand-based virtual screening is described. ROCS 3D-searching gave a favorable chemical motif that was subsequently optimized to arrive at a chemical series of potent and promising SCD1 inhibitors. In particular, compound SAR224 was selected for further pharmacological profiling based on favorable in vitro data. After oral administration to male ZDF rats, this compound significantly decreased the serum fatty acid desaturation index, thus providing conclusive evidence for SCD1 inhibition in vivo by SAR224.