Des-A-ring benzothiadiazines: inhibitors of HCV genotype 1 NS5B RNA-dependent RNA polymerase.
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.
Donner
Pamela L
PL
Antiviral Research, Global Pharmaceutical Research, and Development, Abbott Laboratories, Abbott Park, IL 60064, USA. Pamela.l.donner@abbott.com
Xie
Qinghua
Q
Pratt
John K
JK
Maring
Clarence J
CJ
Kati
Warren
W
Jiang
Wen
W
Liu
Yaya
Y
Koev
Gennadiy
G
Masse
Sherie
S
Montgomery
Debra
D
Molla
Akhter
A
Kempf
Dale J
DJ
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
D001581:Benzothiadiazines; D004791:Enzyme Inhibitors; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase