Synthesis, antiviral activity, and pharmacokinetic evaluation of P3 pyridylmethyl analogs of oximinoarylsulfonyl HIV-1 protease inhibitors

As a continuation of the recently communicated discovery of oximinoarylsulfonamides as potent inhibitors of HIV-1 aspartyl protease, compounds bearing pyridylmethyl substituents at P3 were designed and synthesized. Potent analogs in this series provided low single-digit nanomolar EC50 values against both wild-type HIV and resistant mutant virus (A17), attenuated some 3- to 12-fold in the presence of 50% human serum. Pharmacokinetic results for compounds in this series showed good to excellent exposure when co-administered orally with an equal amount of ritonavir (5 mg/kg each) in the rat, with average AUC >8 μg h/mL. Similar dosing in dog resulted in significantly lower plasma levels (average AUC <2 μg h/mL). The 3-pyridylmethyl analog 30 gave the best overall exposure (rat AUC = 7.1 μg h/mL and dog AUC = 4.9 μg h/mL), however, this compound was found to be a potent inhibitor of cytochrome P450 3A (Ki = 2.4 nM).

A series of potent inhibitors of HIV-1 protease designed to be equally effective at inhibiting both wild-type virus and a mutant strain of virus (A17) highly resistant to lopinavir is described.Figure optionsDownload as PowerPoint slide