Potent Inhibitors of Hepatitis C Virus NS3 Protease: Employment of a Difluoromethyl Group as a Hydrogen-Bond Donor.

Autor: Zheng B; Research and Development, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, Connecticut 06492, United States., D'Andrea SV; Research and Development, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, Connecticut 06492, United States., Sun LQ; Research and Development, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, Connecticut 06492, United States., Wang AX; Research and Development, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, Connecticut 06492, United States., Chen Y; Research and Development, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, Connecticut 06492, United States., Hrnciar P; Research and Development, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, Connecticut 06492, United States., Friborg J; Research and Development, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, Connecticut 06492, United States., Falk P; Research and Development, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, Connecticut 06492, United States., Hernandez D; Research and Development, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, Connecticut 06492, United States., Yu F; Research and Development, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, Connecticut 06492, United States., Sheaffer AK; Research and Development, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, Connecticut 06492, United States., Knipe JO; Research and Development, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, Connecticut 06492, United States., Mosure K; Research and Development, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, Connecticut 06492, United States., Rajamani R; Research and Development, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, Connecticut 06492, United States., Good AC; Research and Development, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, Connecticut 06492, United States., Kish K; Research and Development, Bristol-Myers Squibb, PO Box 5400, Princeton, New Jersey 08543, United States., Tredup J; Research and Development, Bristol-Myers Squibb, PO Box 5400, Princeton, New Jersey 08543, United States., Klei HE; Research and Development, Bristol-Myers Squibb, PO Box 5400, Princeton, New Jersey 08543, United States., Paruchuri M; Biologics Process Development, Bristol-Myers Squibb, 311 Pennington Rocky Hill Road, Pennington, New Jersey 08534, United States., Ng A; Research and Development, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, Connecticut 06492, United States., Gao Q; Research and Development, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, Connecticut 06492, United States., Rampulla RA; Discovery Synthesis, Research and Development, Bristol-Myers Squibb, Route 206 and Province Line Road, Princeton, New Jersey 08543, United States., Mathur A; Discovery Synthesis, Research and Development, Bristol-Myers Squibb, Route 206 and Province Line Road, Princeton, New Jersey 08543, United States., Meanwell NA; Research and Development, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, Connecticut 06492, United States., McPhee F; Research and Development, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, Connecticut 06492, United States., Scola PM; Research and Development, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
Jazyk: angličtina
Zdroj: ACS medicinal chemistry letters [ACS Med Chem Lett] 2018 Jan 19; Vol. 9 (2), pp. 143-148. Date of Electronic Publication: 2018 Jan 19 (Print Publication: 2018).
DOI: 10.1021/acsmedchemlett.7b00503
Abstrakt: 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.
Competing Interests: The authors declare no competing financial interest.
Databáze: MEDLINE
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