Imidazopyridazine hepatitis C virus polymerase inhibitors. Structure-activity relationship studies and the discovery of a novel, traceless prodrug mechanism.
By reducing the basicity of the core heterocycle in a series of HCV NS5B inhibitors, the hERG liability was reduced. The SAR was then systematically explored in order to increase solubility and enable dose escalation while retaining potency. During this exploration, a facile decarboxylation was noted and was exploited as a novel prodrug mechanism. The synthesis and characterization of these prodrugs and their utilization in chronic toxicity studies are presented.
GlaxoSmithKline Research & Development , 5 Moore Drive, Research Triangle Park, North Carolina 27709, United States.
Martin
M
Leivers
John F
JF
Miller
Stephanie A
SA
Chan
Ryan
R
Lauchli
Sebastian
S
Liehr
Wenyan
W
Mo
Tony
T
Ton
Elizabeth M
EM
Turner
Michael
M
Youngman
J Greg
JG
Falls
Susan
S
Long
Amanda
A
Mathis
Jill
J
Walker
D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D004285:Dogs; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D011724:Pyridazines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D011724:Pyridazines; D017361:Viral Nonstructural Proteins; C062482:pyridazine; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase