Discovery, SAR study and ADME properties of methyl 4-amino-3-cyano-1-(2-benzyloxyphenyl)-1 H-pyrazole-5-carboxylate as an HIV-1 replication inhibitor

RSC Med Chem. 2020 Apr 27;11(5):577-582. doi: 10.1039/d0md00025f. eCollection 2020 May 1.


Inspired by the antiviral activity of known pyrazole-based HIV inhibitors, we screened our in-house library of pyrazole-based compounds to evaluate their in cellulo activity against HIV-1 replication. Two hits with very similar structures appeared from single and multiple-round infection assays to be non-toxic and active in a dose-dependent manner. Chemical expansion of their series allowed an in-depth and consistent structure-activity-relationship study (SAR) to be built. Further ADME evaluation led to the selection of 4-amino-3-cyano-1-(2-benzyloxyphenyl)-1H-pyrazole-5-carboxylate with an advantageous pharmacokinetic profile. Finally, examination of its mode of action revealed that this compound does not belong to the three main classes of anti-HIV drugs, a feature of prime interest in the context of viral resistance.