Des-A-ring benzothiadiazines: Inhibitors of HCV genotype 1 NS5B RNA-dependent RNA polymerase

• Published in: Bioorganic & medicinal chemistry 2008-04, Vol.18 (8), p.2735-2738
• Main Authors: Donner, Pamela L., Xie, Qinghua, Pratt, John K., Maring, Clarence J., Kati, Warren, Jiang, Wen, Liu, Yaya, Koev, Gennadiy, Masse, Sherie, Montgomery, Debra, Molla, Akhter, Kempf, Dale J.
• Format: Article
• Language: English
• Subjects: Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antivirals; Benzothiadiazines; Benzothiadiazines - chemical synthesis; Benzothiadiazines - chemistry; Benzothiadiazines - pharmacology; Biological and medical sciences; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Genotype; HCV genotype 1; HCV polymerase; Hepacivirus - enzymology; Hepatitis C virus; Medical sciences; Models, Molecular; Molecular Structure; Pharmacology. Drug treatments; RNA-Dependent RNA Polymerase - antagonists & inhibitors; RNA-Dependent RNA Polymerase - chemistry; RNA-Dependent RNA Polymerase - metabolism; Structure-Activity Relationship; Viral Nonstructural Proteins - antagonists & inhibitors; Viral Nonstructural Proteins - chemistry; Viral Nonstructural Proteins - metabolism; Virus Replication - drug effects
• ISSN: 0960-894X; 0968-0896; 1464-3405; 1464-3391
• DOI: 10.1016/j.bmcl.2008.02.064

Described herein is a set of non-nucleoside, small molecule inhibitors of genotype 1 HCV polymerase based on a benzothiadiazine screening hit. After demonstrating that a methylsulfonylamino D-ring substituent increased the enzyme potency into the low nanomolar range, a minimum core required for activity was explored. We observed that small aromatic rings and alkenyl groups appended to the 5-position of the B-ring were optimal, resulting in inhibitors with low nanomolar potencies. In our program to discover non-nucleoside, small molecule inhibitors of genotype 1 HCV polymerase, we investigated a series of promising analogs based on a benzothiadiazine screening hit that contains an ABCD ring system. After demonstrating that a methylsulfonylamino D-ring substituent increased the enzyme potency into the low nanomolar range, we explored a minimum core required for activity by truncating to a three-ring system. Described herein are the syntheses and structure–activity relationship of a set of inhibitors lacking the A-ring of an ABCD ring system. We observed that small aromatic rings and alkenyl groups appended to the 5-position of the B-ring were optimal, resulting in inhibitors with low nanomolar potencies.