| Literature DB >> 29456803 |
Barbara Zheng1, Stanley V D'Andrea1, Li-Qiang Sun1, Alan Xiangdong Wang1, Yan Chen1, Peter Hrnciar1, Jacques Friborg1, Paul Falk1, Dennis Hernandez1, Fei Yu1, Amy K Sheaffer1, Jay O Knipe1, Kathy Mosure1, Ramkumar Rajamani1, Andrew C Good1, Kevin Kish2, Jeffrey Tredup2, Herbert E Klei2, Manjula Paruchuri3, Alicia Ng1, Qi Gao1, Richard A Rampulla4, Arvind Mathur4, Nicholas A Meanwell1, Fiona McPhee1, Paul M Scola1.
Abstract
The design and synthesis of potent, tripeptidic acylsulfonamide inhibitors of HCV NS3 protease that contain a difluoromethyl cyclopropyl amino acid at P1 are described. A cocrystal structure of 18 with a NS3/4A protease complex suggests the presence of a H-bond between the polarized C-H of the CHF2 moiety and the backbone carbonyl of Leu135 of the enzyme. Structure-activity relationship studies indicate that this H-bond enhances enzyme inhibitory potency by 13- and 17-fold compared to the CH3 and CF3 analogues, respectively, providing insight into the deployment of this unique amino acid.Entities:
Year: 2018 PMID： 29456803 PMCID： PMC5807875 DOI： 10.1021/acsmedchemlett.7b00503
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345