2. Academic Validation
  3. Minimizing the Contribution of Enterohepatic Recirculation to Clearance in Rat for the NCINI Class of Inhibitors of HIV

Minimizing the Contribution of Enterohepatic Recirculation to Clearance in Rat for the NCINI Class of Inhibitors of HIV

  • ACS Med Chem Lett. 2014 Apr 16;5(6):711-6. doi: 10.1021/ml500110j.
Lee D Fader 1,  Rebekah Carson 1,  Sébastien Morin 1,  François Bilodeau 1,  Catherine Chabot 1,  Ted Halmos 1,  Murray D Bailey 1,  Stephen H Kawai 1,  René Coulombe 1,  Steven Laplante 1,  Kevork Mekhssian 1,  Araz Jakalian 1,  Michel Garneau 1,  Jianmin Duan 1,  Stephen W Mason 1,  Bruno Simoneau 1,  Craig Fenwick 1,  Youla Tsantrizos 1,  Christiane Yoakim 1
Affiliations

Affiliation

  • 1 Research and Development, Boehringer Ingelheim (Canada), Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
PMID: 24944749 DOI: 10.1021/ml500110j
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.

Keywords

NCINI; biliary excretion; enterohepatic recirculation; integrase tetramer.

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