Discovery of a Series of Phosphonic Acid-Containing Thiazoles and Orally Bioavailable Diamide Prodrugs That Lower Glucose in Diabetic Animals Through Inhibition of Fructose-1,6-Bisphosphatase

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• 作者：Qun Dang ; Yan Liu ; Daniel K. Cashion ; Srinivas Rao Kasibhatla ; Tao Jiang ; Frank Taplin ; Jason D. Jacintho ; Haiqing Li ; Zhili Sun ; Yi Fan ; Jay DaRe ; Feng Tian ; Wenyu Li ; Tony Gibson ; Robert Lemus ; Paul D. van Poelje ; Scott C. Potter ; Mark D. Erion
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：January 13, 2011
• 年：2011
• 卷：54
• 期：1
• 页码：153-165
• 全文大小：1055K
• 年卷期：v.54,no.1(January 13, 2011)
• ISSN：1520-4804

文摘

Oral delivery of previously disclosed purine and benzimidazole fructose-1,6-bisphosphatase (FBPase) inhibitors via prodrugs failed, which was likely due to their high molecular weight (>600). Therefore, a smaller scaffold was desired, and a series of phosphonic acid-containing thiazoles, which exhibited high potency against human liver FBPase (IC₅₀ of 10鈭?0 nM) and high selectivity relative to other 5鈥?adenosinemonophosphate (AMP)-binding enzymes, were discovered using a structure-guided drug design approach. The initial lead compound (30j) produced profound glucose lowering in rodent models of type 2 diabetes mellitus (T2DM) after parenteral administration. Various phosphonate prodrugs were explored without success, until a novel phosphonic diamide prodrug approach was implemented, which delivered compound 30j with good oral bioavailability (OBAV) (22鈭?7%). Extensive lead optimization of both the thiazole FBPase inhibitors and their prodrugs culminated in the discovery of compound 35n (MB06322) as the first oral FBPase inhibitor advancing to human clinical trials as a potential treatment for T2DM.