Free-Wilson and Structural Approaches to Co-optimizing Human and Rodent Isoform Potency for 11尾-Hydroxysteroid Dehydrogenase Type 1 (11尾-HSD1) Inhibitors

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• 作者：Frederick W. Goldberg ; Andrew G. Leach ; James S. Scott ; Wendy L. Snelson ; Sam D. Groombridge ; Craig S. Donald ; Stuart N. L. Bennett ; Cristian Bodin ; Pablo Morentin Gutierrez ; Amy C. Gyte
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：December 13, 2012
• 年：2012
• 卷：55
• 期：23
• 页码：10652-10661
• 全文大小：514K
• 年卷期：v.55,no.23(December 13, 2012)
• ISSN：1520-4804

文摘

11尾-Hydroxysteroid dehydrogenase 1 (11尾-HSD1) has been a target of intensive research efforts across the pharmaceutical industry, due to its potential for the treatment of type II diabetes and other elements of the metabolic syndrome. To demonstrate the value of 11尾-HSD1 in preclinical models, we required inhibitors with good potency against both human and rodent isoforms. Herein, we describe our efforts to understand how to co-optimize human and murine potency within the (5-hydroxy-2-adamantyl)-pyrimidine-5-carboxamide series. Two approaches are described鈥攁 data-driven (Free-Wilson) analysis and a structure-based design approach. The conclusions from these approaches were used to inform an efficient campaign to design compounds with consistently good human/murine potency within a logD_7.4 range of 1鈥?. Compounds 20 and 26 demonstrated good rodent PK, which allowed us to demonstrate a PK/PD relationship in rat and mouse. We then evaluated 26 against glycemic and body weight end points in murine disease models, where it demonstrated glucose and body weight efficacy at 300 mg/kg/day but only body weight efficacy at 50 mg/kg/day, despite providing >90% target engagement in the liver.