Discovery of (S)-6-(3-Cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinic Acid as a Hepatoselective Glucokinase Activator Clinical Candidate for Treating Type 2 Dia

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• 作者：Jeffrey A. Pfefferkorn ; Angel Guzman-Perez ; John Litchfield ; Robert Aiello ; Judith L. Treadway ; John Pettersen ; Martha L. Minich ; Kevin J. Filipski ; Christopher S. Jones ; Meihua Tu ; Gary Aspnes ; Hud Risley ; Jianwei Bian ; Benjamin D. Stevens ; Patricia Bourassa ; Theresa D鈥橝quila ; Levenia Baker ; Nicole Barucci ; Alan S. Robertson ; Francis Bourbonais ; David R. Derksen ; Margit MacDougall ; Over Cabrera ; Jing Chen ; Amanda Lee Lapworth ; James A. Landro ; William J. Zavadoski ; Karen Atkinson ; Nahor Haddish-Berhane ; Beijing Tan ; Lili Yao ; Rachel E. Kosa ; Manthena V. Varma ; Bo Feng ; David B. Duignan ; Ayman El-Kattan ; Sharad Murdande ; Shenping Liu ; Mark Ammirati ; John Knafels ; Paul DaSilva-Jardine ; Laurel Sweet ; Spiros Liras ; Timothy P. Rolph
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：February 9, 2012
• 年：2012
• 卷：55
• 期：3
• 页码：1318-1333
• 全文大小：555K
• 年卷期：v.55,no.3(February 9, 2012)
• ISSN：1520-4804

文摘

Glucokinase is a key regulator of glucose homeostasis, and small molecule allosteric activators of this enzyme represent a promising opportunity for the treatment of type 2 diabetes. Systemically acting glucokinase activators (liver and pancreas) have been reported to be efficacious but in many cases present hypoglycaemia risk due to activation of the enzyme at low glucose levels in the pancreas, leading to inappropriately excessive insulin secretion. It was therefore postulated that a liver selective activator may offer effective glycemic control with reduced hypoglycemia risk. Herein, we report structure鈥揳ctivity studies on a carboxylic acid containing series of glucokinase activators with preferential activity in hepatocytes versus pancreatic 尾-cells. These activators were designed to have low passive permeability thereby minimizing distribution into extrahepatic tissues; concurrently, they were also optimized as substrates for active liver uptake via members of the organic anion transporting polypeptide (OATP) family. These studies lead to the identification of 19 as a potent glucokinase activator with a greater than 50-fold liver-to-pancreas ratio of tissue distribution in rodent and non-rodent species. In preclinical diabetic animals, 19 was found to robustly lower fasting and postprandial glucose with no hypoglycemia, leading to its selection as a clinical development candidate for treating type 2 diabetes.