title: Discovery and preclinical evaluation of potent, orally bioavailable, metabolically stable cyclopropylindolobenzazepine acylsulfonamides as thumb site 1 inhibitors of the hepatitis c virus NS5B RNA-dependent, RNA polymerase.
abstract: Herein, we describe the synthesis, antiviral structure-activity relationships (SAR), metabolic stability, and pharmacokinetic (PK) properties for a series of cyclopropylindolobenzazepine acylsulfonamide HCV NS5B polymerase inhibitors. Optimization of SAR, metabolic stability and PK led to the identification of compound 19 which was advanced into pre-IND enabling toxicology studies.
authors.affiliation: Department of Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States. Electronic address: hewawasp@gmail.com.
authors.forename: Piyasena
authors.initials: P
authors.lastname: Hewawasam
authors.affiliation: Department of Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Yong
authors.initials: Y
authors.lastname: Tu
authors.affiliation: Department of Virology, Bristol-Myers Squibb Pharmaceutical Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Min
authors.initials: M
authors.lastname: Gao
authors.affiliation: Preclinical Candidate Optimization, Bristol-Myers Squibb Pharmaceutical Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Umesh
authors.initials: U
authors.lastname: Hanumegowda
authors.affiliation: Preclinical Candidate Optimization, Bristol-Myers Squibb Pharmaceutical Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Jay
authors.initials: J
authors.lastname: Knipe
authors.affiliation: Department of Virology, Bristol-Myers Squibb Pharmaceutical Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Lemm
authors.affiliation: Preclinical Candidate Optimization, Bristol-Myers Squibb Pharmaceutical Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Dawn D
authors.initials: DD
authors.lastname: Parker
authors.affiliation: Department of Virology, Bristol-Myers Squibb Pharmaceutical Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Rigat
authors.affiliation: Department of Virology, Bristol-Myers Squibb Pharmaceutical Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Susan B
authors.initials: SB
authors.lastname: Roberts
authors.affiliation: Department of Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical 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 Pharmaceutical Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: John F
authors.initials: JF
authors.lastname: Kadow
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D001552:Benzazepines / Q000737:chemistry; D004353:Drug Evaluation, Preclinical; D006207:Half-Life; D016174:Hepacivirus / Q000201:enzymology*; D006801:Humans; D008252:Macaca fascicularis; D008862:Microsomes, Liver / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics
chemical_list: D000998:Antiviral Agents; D001552:Benzazepines; D013449:Sulfonamides; D012324:RNA-Dependent RNA Polymerase
keywords: Antiviral agent; Cyclopropylindolobenzazepine; Direct-acting; HCV; Inhibitors; NS5B; Replicase