Structure-activity relationships of 4-hydroxy-4-biaryl-proline acylsulfonamide tripeptides: A series of potent NS3 protease inhibitors for the treatment of hepatitis C virus

Alan Xiangdong Wang; Jie Chen; Qian Zhao; Li-Qiang Sun; Jacques Friborg; Fei Yu; Dennis Hernandez; Andrew C Good; Herbert E Klei; Ramkumar Rajamani; Kathy Mosure; Jay O Knipe; Danshi Li; Jialong Zhu; Paul C Levesque; Fiona McPhee; Nicholas A Meanwell; Paul M Scola

doi:10.1016/j.bmcl.2016.12.013

Structure-activity relationships of 4-hydroxy-4-biaryl-proline acylsulfonamide tripeptides: A series of potent NS3 protease inhibitors for the treatment of hepatitis C virus

Bioorg Med Chem Lett. 2017 Feb 1;27(3):590-596. doi: 10.1016/j.bmcl.2016.12.013. Epub 2016 Dec 9.

Authors

Alan Xiangdong Wang¹, Jie Chen², Qian Zhao², Li-Qiang Sun², Jacques Friborg³, Fei Yu³, Dennis Hernandez³, Andrew C Good⁴, Herbert E Klei⁴, Ramkumar Rajamani⁴, Kathy Mosure⁵, Jay O Knipe⁵, Danshi Li⁵, Jialong Zhu⁵, Paul C Levesque⁵, Fiona McPhee³, Nicholas A Meanwell², Paul M Scola²

Affiliations

¹ Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States. Electronic address: alan.wang@bms.com.
² Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
³ Department of Virology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
⁴ Department of Computational-Aided Drug Design, Bristol-Myers Squibb Research and Development, Research Parkway, Wallingford, CT 06492, United States.
⁵ Global Clinical Research, Bristol-Myers Squibb Research and Development, 5, Research Parkway, Wallingford, CT 06492, United States.

PMID: 28011221
DOI: 10.1016/j.bmcl.2016.12.013

Abstract

The design and synthesis of a series of tripeptide acylsulfonamides as potent inhibitors of the HCV NS3/4A serine protease is described. These analogues house a C4 aryl, C4 hydroxy-proline at the S2 position of the tripeptide scaffold. Information relating to structure-activity relationships as well as the pharmacokinetic and cardiovascular profiles of these analogues is provided.

Keywords: C4 aryl, C4 hydroxy-proline; Cardiovascular profiles; HCV NS3/4A serine protease inhibitors; Potent and orally bioavailable; Tripeptide acylsulfonamides.

MeSH terms

Animals
Antiviral Agents / chemistry*
Antiviral Agents / pharmacokinetics
Antiviral Agents / pharmacology
Half-Life
Heart / drug effects
Hepacivirus / drug effects
Hepacivirus / enzymology*
Humans
In Vitro Techniques
Oligopeptides / chemistry*
Oligopeptides / pharmacokinetics
Oligopeptides / pharmacology
Proline / chemistry
Protease Inhibitors / chemistry*
Protease Inhibitors / pharmacokinetics
Protease Inhibitors / pharmacology
Rabbits
Rats
Structure-Activity Relationship
Sulfonamides / chemistry
Viral Nonstructural Proteins / antagonists & inhibitors*
Viral Nonstructural Proteins / metabolism

Substances

Antiviral Agents
NS3 protein, hepatitis C virus
Oligopeptides
Protease Inhibitors
Sulfonamides
Viral Nonstructural Proteins
Proline