Minimizing the Contribution of Enterohepatic Recirculation to Clearance in Rat for the NCINI Class of Inhibitors of HIV.
Lee D Fader, Rebekah Carson, Sébastien Morin, François Bilodeau, Catherine Chabot, Ted Halmos, Murray D Bailey, Stephen H Kawai, René Coulombe, Steven Laplante, Kevork Mekhssian, Araz Jakalian, Michel Garneau, Jianmin Duan, Stephen W Mason, Bruno Simoneau, Craig Fenwick, Youla Tsantrizos, Christiane Yoakim
Author Information
Lee D Fader: Research and Development, Boehringer Ingelheim (Canada), Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
Rebekah Carson: Research and Development, Boehringer Ingelheim (Canada), Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
Sébastien Morin: Research and Development, Boehringer Ingelheim (Canada), Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
François Bilodeau: Research and Development, Boehringer Ingelheim (Canada), Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
Catherine Chabot: Research and Development, Boehringer Ingelheim (Canada), Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
Ted Halmos: Research and Development, Boehringer Ingelheim (Canada), Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
Murray D Bailey: Research and Development, Boehringer Ingelheim (Canada), Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
Stephen H Kawai: Research and Development, Boehringer Ingelheim (Canada), Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
René Coulombe: Research and Development, Boehringer Ingelheim (Canada), Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
Steven Laplante: Research and Development, Boehringer Ingelheim (Canada), Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
Kevork Mekhssian: Research and Development, Boehringer Ingelheim (Canada), Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
Araz Jakalian: Research and Development, Boehringer Ingelheim (Canada), Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
Michel Garneau: Research and Development, Boehringer Ingelheim (Canada), Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
Jianmin Duan: Research and Development, Boehringer Ingelheim (Canada), Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
Stephen W Mason: Research and Development, Boehringer Ingelheim (Canada), Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
Bruno Simoneau: Research and Development, Boehringer Ingelheim (Canada), Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
Craig Fenwick: Research and Development, Boehringer Ingelheim (Canada), Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
Youla Tsantrizos: Research and Development, Boehringer Ingelheim (Canada), Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
Christiane Yoakim: Research and Development, Boehringer Ingelheim (Canada), Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
A scaffold replacement approach was used to identifying the pyridine series of noncatalytic site integrase inhibitors. These molecules bind with higher affinity to a tetrameric form compared to a dimeric form of integrase. Optimization of the C6 and C4 positions revealed that viruses harboring T124 or A124 amino acid substitutions are highly susceptible to these inhibitors, but viruses having the N124 amino acid substitution are about 100-fold less susceptible. Compound 20 had EC50 values <10 nM against viruses having T124 or A124 substitutions in IN and >800 nM in viruses having N124 substitions. Compound 20 had an excellent in vitro ADME profile and demonstrated reduced contribution of biliary excretion to in vivo clearance compared to BI 224436, the lead compound from the quinoline series of NCINIs.
