Discovery of BI 207524, an indole diamide NS5B thumb pocket 1 inhibitor with improved potency for the potential treatment of chronic hepatitis C virus infection.
The development of interferon-free regimens for the treatment of chronic HCV infection constitutes a preferred option that is expected in the future to provide patients with improved efficacy, better tolerability, and reduced risk for emergence of drug-resistant virus. We have pursued non-nucleoside NS5B polymerase allosteric inhibitors as combination partners with other direct acting antivirals (DAAs) having a complementary mechanism of action. Herein, we describe the discovery of a potent follow-up compound (BI 207524, 27) to the first thumb pocket 1 NS5B inhibitor to demonstrate antiviral activity in genotype 1 HCV infected patients, BILB 1941 (1). Cell-based replicon potency was significantly improved through electronic modulation of the pKa of the carboxylic acid function of the lead molecule. Subsequent ADME-PK optimization lead to 27, a predicted low clearance compound in man. The preclinical profile of inhibitor 27 is discussed, as well as the identification of a genotoxic metabolite that led to the discontinuation of the development of this compound.
Boehringer Ingelheim (Canada) Ltd. , Research and Development, 2100 Cunard Street, Laval, Quebec H7S 2G5, Canada.
Pierre L
PL
Beaulieu
Paul C
PC
Anderson
Richard
R
Bethell
Michael
M
Bös
Yves
Y
Bousquet
Christian
C
Brochu
Michael G
MG
Cordingley
Gulrez
G
Fazal
Michel
M
Garneau
James R
JR
Gillard
Stephen
S
Kawai
Martin
M
Marquis
Ginette
G
McKercher
Marc-André
MA
Poupart
Timothy
T
Stammers
Bounkham
B
Thavonekham
Dominik
D
Wernic
Jianmin
J
Duan
George
G
Kukolj
D000179:Acrylates / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000378:metabolism* / Q000494:pharmacology; D002934:Cinnamates / Q000138:chemical synthesis / Q000378:metabolism / Q000493:pharmacokinetics; D004285:Dogs; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000493:pharmacokinetics; D019698:Hepatitis C, Chronic; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics; D008253:Macaca mulatta; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors; D051381:Rats; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*
C000595474:(E)-3-(4-((1-((2-(5-chloro-pyrimidin-2-yl)-3-cyclopentyl-1-methyl-1H-indole-6-carbonyl)-amino)-cyclobutanecarbonyl)-amino)-2-ethoxy-phenyl)-acrylic acid; D000179:Acrylates; D000998:Antiviral Agents; D002934:Cinnamates; D004791:Enzyme Inhibitors; D007211:Indoles; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase