1 research outputs found
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