title: Des-A-ring benzothiadiazines: inhibitors of HCV genotype 1 NS5B RNA-dependent RNA polymerase.
abstract: 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.
authors: Antiviral Research, Global Pharmaceutical Research, and Development, Abbott Laboratories, Abbott Park, IL 60064, USA. Pamela.l.donner@abbott.com
authors: Pamela L
authors: PL
authors: Donner
authors: Qinghua
authors: Q
authors: Xie
authors: John K
authors: JK
authors: Pratt
authors: Clarence J
authors: CJ
authors: Maring
authors: Warren
authors: W
authors: Kati
authors: Wen
authors: W
authors: Jiang
authors: Yaya
authors: Y
authors: Liu
authors: Gennadiy
authors: G
authors: Koev
authors: Sherie
authors: S
authors: Masse
authors: Debra
authors: D
authors: Montgomery
authors: Akhter
authors: A
authors: Molla
authors: Dale J
authors: DJ
authors: Kempf
mesh_terms: D001581:Benzothiadiazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D005838:Genotype; D016174:Hepacivirus / Q000201:enzymology*; D008958:Models, Molecular; D015394:Molecular Structure; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
chemical_list: D001581:Benzothiadiazines; D004791:Enzyme Inhibitors; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase