2 research outputs found
Minimizing the Contribution of Enterohepatic Recirculation to Clearance in Rat for the NCINI Class of Inhibitors of HIV
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 <b>20</b> had
EC<sub>50</sub> values <10 nM against viruses having T124 or A124
substitutions in IN and >800 nM in viruses having N124 substitions.
Compound <b>20</b> 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
Aligning Potency and Pharmacokinetic Properties for Pyridine-Based NCINIs
Optimization
of pyridine-based noncatalytic site integrase inhibitors (NCINIs)
based on compound <b>2</b> has led to the discovery of molecules
capable of inhibiting virus harboring N124 variants of HIV integrase
(IN) while maintaining minimal contribution of enterohepatic recirculation
to clearance in rat. Structure–activity relationships at the
C6 position established chemical space where the extent of enterohepatic
recirculation in the rat is minimized. Desymmetrization of the C4
substituent allowed for potency optimization against virus having
the N124 variant of integrase. Combination of these lessons led to
the discovery of compound <b>20</b>, having balanced serum-shifted
antiviral potency and minimized excretion in to the biliary tract
in rat, potentially representing a clinically viable starting point
for a new treatment option for individuals infected with HIV