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Discovery and optimization of orally active cyclohexane-based prolylcarboxypeptidase (PrCP) inhibitors |
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| Authors: | John S Debenham Thomas H Graham Andreas Verras Yong Zhang Matthew J Clements Jeffrey T Kuethe Christina Madsen-Duggan Wensheng Liu Urmi R Bhatt Dunlu Chen Qing Chen Margarita Garcia-Calvo Wayne M Geissler Huaibing He Xiaohua Li JeanMarie Lisnock Zhu Shen Xinchun Tong Dong-Ming Shen |
| Institution: | 1. Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA;2. Department of Process Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA;3. Department of Metabolic Disorders, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA;4. Department of Drug Metabolism, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA;5. Department of In Vitro Sciences, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA |
| Abstract: | The synthesis, SAR, binding affinities and pharmacokinetic profiles are described for a series of cyclohexane-based prolylcarboxypeptidase (PrCP) inhibitors discovered by high throughput screening. Compounds show high levels of ex vivo target engagement in mouse plasma 20 h post oral dose. |
| Keywords: | PrCP Prolylcarboxypeptidase Serine protease Inhibitor Obesity |
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