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

Piyasena Hewawasam; Yong Tu; Min Gao; Umesh Hanumegowda; Jay Knipe; Julie A Lemm; Dawn D Parker; Karen L Rigat; Susan B Roberts; Nicholas A Meanwell; John F Kadow

doi:10.1016/j.bmcl.2015.12.058

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

Bioorg Med Chem Lett. 2016 Feb 1;26(3):936-940. doi: 10.1016/j.bmcl.2015.12.058. Epub 2015 Dec 19.

Authors

Affiliations

¹ Department of Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States. Electronic address: hewawasp@gmail.com.
² Department of Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
³ Department of Virology, Bristol-Myers Squibb Pharmaceutical Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
⁴ Preclinical Candidate Optimization, Bristol-Myers Squibb Pharmaceutical Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.

PMID: 26747393
DOI: 10.1016/j.bmcl.2015.12.058

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.

Keywords: Antiviral agent; Cyclopropylindolobenzazepine; Direct-acting; HCV; Inhibitors; NS5B; Replicase.

MeSH terms

Administration, Oral
Animals
Antiviral Agents / chemical synthesis
Antiviral Agents / chemistry*
Antiviral Agents / pharmacokinetics
Benzazepines / chemistry
Drug Evaluation, Preclinical
Half-Life
Hepacivirus / enzymology*
Humans
Macaca fascicularis
Microsomes, Liver / metabolism
RNA-Dependent RNA Polymerase / antagonists & inhibitors*
RNA-Dependent RNA Polymerase / metabolism
Rats
Structure-Activity Relationship
Sulfonamides / chemical synthesis
Sulfonamides / chemistry*
Sulfonamides / pharmacokinetics

Substances

Antiviral Agents
Benzazepines
Sulfonamides
RNA-Dependent RNA Polymerase