Design, Synthesis, and Preclinical Profiling of GSK3739936 (BMS-986180), an Allosteric Inhibitor of HIV‑1 Integrase with Broad-Spectrum Activity toward 124/125 Polymorphs

Allosteric
HIV-1 integrase inhibitors (ALLINIs) have garnered special
interest because of their novel mechanism of action: they inhibit
HIV-1 replication by promoting aberrant integrase multimerization,
leading to the production of replication-deficient viral particles.
The binding site of ALLINIs is in a well-defined pocket formed at
the interface of two integrase monomers that is characterized by conserved
residues along with two polymorphic amino acids at residues 124 and
125. The design, synthesis, and optimization of pyridine-based allosteric
integrase inhibitors are reported here. Optimization was conducted
with a specific emphasis on the inhibition of the 124/125 polymorphs
such that the designed compounds showed excellent potency in vitro against majority of the 124/125 variants. In vivo profiling of promising preclinical lead 29 showed that it exhibited a good pharmacokinetic (PK) profile in
preclinical species, which resulted in a low predicted human efficacious
dose. However, findings in rat toxicology studies precluded further
development of 29.