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A new class of prolylcarboxypeptidase inhibitors, part 1: discovery and evaluation |
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| Authors: | Graham Thomas H Liu Wensheng Verras Andreas Sebhat Iyassu K Xiong Yusheng Bleasby Kelly Bhatt Urmi R Chen Qing Garcia-Calvo Margarita Geissler Wayne M Gorski Judith N He Huaibing Lassman Michael E Lisnock JeanMarie Li Xiaohua Shen Zhu Tong Xinchun Tung Elaine C Wiltsie Judyann Xiao Jianying Xie Dan Xu Suoyu Hale Jeffrey J Pinto Shirly Shen Dong-Ming |
| Institution: | Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065-0900, USA. thomas.graham@merck.com |
| Abstract: | A new structural class of potent prolylcarboxypeptidase (PrCP) inhibitors was discovered by high-throughput screening. The series possesses a tractable SAR profile with sub-nanomolar in vitro IC(50) values. Compared to prior inhibitors, the new series demonstrated minimal activity shifts in pure plasma and complete ex vivo plasma target engagement in mouse plasma at the 20 h post-dose time point (po). In addition, the in vivo level of CNS and non-CNS drug exposure was measured. |
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