title: Minimizing the Contribution of Enterohepatic Recirculation to Clearance in Rat for the NCINI Class of Inhibitors of HIV.
abstract: 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.
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada), Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Lee D
authors.initials: LD
authors.lastname: Fader
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada), Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Rebekah
authors.initials: R
authors.lastname: Carson
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada), Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Morin
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada), Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: François
authors.initials: F
authors.lastname: Bilodeau
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada), Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Catherine
authors.initials: C
authors.lastname: Chabot
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada), Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Ted
authors.initials: T
authors.lastname: Halmos
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada), Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Murray D
authors.initials: MD
authors.lastname: Bailey
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada), Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Kawai
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada), Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: René
authors.initials: R
authors.lastname: Coulombe
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada), Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Steven
authors.initials: S
authors.lastname: Laplante
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada), Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Kevork
authors.initials: K
authors.lastname: Mekhssian
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada), Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Araz
authors.initials: A
authors.lastname: Jakalian
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada), Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Michel
authors.initials: M
authors.lastname: Garneau
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada), Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Duan
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada), Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Mason
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada), Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Bruno
authors.initials: B
authors.lastname: Simoneau
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada), Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Craig
authors.initials: C
authors.lastname: Fenwick
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada), Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Youla
authors.initials: Y
authors.lastname: Tsantrizos
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada), Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Christiane
authors.initials: C
authors.lastname: Yoakim
keywords: NCINI; biliary excretion; enterohepatic recirculation; integrase tetramer