title: 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.
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.
authors.affiliation: Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States. Electronic address: alan.wang@bms.com.
authors.forename: Alan Xiangdong
authors.initials: AX
authors.lastname: Wang
authors.affiliation: Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Li-Qiang
authors.initials: LQ
authors.lastname: Sun
authors.affiliation: Department of Virology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Jacques
authors.initials: J
authors.lastname: Friborg
authors.affiliation: Department of Virology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Fei
authors.initials: F
authors.lastname: Yu
authors.affiliation: Department of Virology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Dennis
authors.initials: D
authors.lastname: Hernandez
authors.affiliation: Department of Computational-Aided Drug Design, Bristol-Myers Squibb Research and Development, Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Good
authors.affiliation: Department of Computational-Aided Drug Design, Bristol-Myers Squibb Research and Development, Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Herbert E
authors.initials: HE
authors.lastname: Klei
authors.affiliation: Department of Computational-Aided Drug Design, Bristol-Myers Squibb Research and Development, Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Ramkumar
authors.initials: R
authors.lastname: Rajamani
authors.affiliation: Global Clinical Research, Bristol-Myers Squibb Research and Development, 5, Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Kathy
authors.initials: K
authors.lastname: Mosure
authors.affiliation: Global Clinical Research, Bristol-Myers Squibb Research and Development, 5, Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Jay O
authors.initials: JO
authors.lastname: Knipe
authors.affiliation: Global Clinical Research, Bristol-Myers Squibb Research and Development, 5, Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Danshi
authors.initials: D
authors.lastname: Li
authors.affiliation: Global Clinical Research, Bristol-Myers Squibb Research and Development, 5, Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Jialong
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Global Clinical Research, Bristol-Myers Squibb Research and Development, 5, Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Levesque
authors.affiliation: Department of Virology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Fiona
authors.initials: F
authors.lastname: McPhee
authors.affiliation: Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Meanwell
authors.affiliation: Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Scola
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D006207:Half-Life; D006321:Heart / Q000187:drug effects; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D066298:In Vitro Techniques; D009842:Oligopeptides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D011392:Proline / Q000737:chemistry; D011480:Protease Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D009842:Oligopeptides; D011392:Proline; D011480:Protease Inhibitors; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
keywords: C4 aryl, C4 hydroxy-proline; Cardiovascular profiles; HCV NS3/4A serine protease inhibitors; Potent and orally bioavailable; Tripeptide acylsulfonamides