Open AccessPotent Inhibitors of Hepatitis C Virus NS3 Protease: Employment of a Difluoromethyl Group as a Hydrogen-Bond Donor
Author(s) -
Barbara Zheng,
Stanley V. D’Andrea,
LiQiang Sun,
Alan Xiangdong Wang,
Yan Chen,
P. Hrnčiar,
Jacques Friborg,
Paul Falk,
Dennis Hernandez,
Fei Yu,
Amy K. Sheaffer,
Jay O. Knipe,
Kathy Mosure,
Ramkumar Rajamani,
Andrew C. Good,
Kevin Kish,
Jeffrey Tredup,
Herbert E. Klei,
Manjula Paruchuri,
Alicia Ng,
Qi Gao,
Richard Rampulla,
Arvind Mathur,
Nicholas A. Meanwell,
Fiona McPhee,
Paul M. Scola
Publication year - 2018
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.7b00503
Subject(s) - moiety , ns3 , protease , chemistry , hydrogen bond , stereochemistry , cocrystal , enzyme , potency , hepatitis c virus , amino acid , virology , biochemistry , virus , medicine , in vitro , organic chemistry , molecule
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 CHF 2 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 CH 3 and CF 3 analogues, respectively, providing insight into the deployment of this unique amino acid.