ml500110j_si_001.pdf (77.07 kB)
Minimizing the Contribution of Enterohepatic Recirculation to Clearance in Rat for the NCINI Class of Inhibitors of HIV
journal contribution
posted on 2014-06-12, 00:00 authored by 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 YoakimA 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.