Discovery and optimization of orally active cyclohexane-based prolylcarboxypeptidase (PrCP) inhibitors

…, MJ Clements, JT Kuethe, C Madsen-Duggan…

Index: Debenham, John S.; Graham, Thomas H.; Verras, Andreas; Zhang, Yong; Clements, Matthew J.; Kuethe, Jeffrey T.; Madsen-Duggan, Christina; Liu, Wensheng; Bhatt, Urmi R.; Chen, Dunlu; Chen, Qing; Garcia-Calvo, Margarita; Geissler, Wayne M.; He, Huaibing; Li, Xiaohua; Lisnock, Jeanmarie; Shen, Zhu; Tong, Xinchun; Tung, Elaine C.; Wiltsie, Judyann; Xu, Suoyu; Hale, Jeffrey J.; Pinto, Shirly; Shen, Dong-Ming Bioorganic and Medicinal Chemistry Letters, 2013 , vol. 23, # 23 p. 6228 - 6233

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Abstract

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.