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

Bioorganic & Medicinal Chemistry
John T RandolphD J Kempf

Abstract

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 (5mg/kg each) in the rat, with average AUC >8 microg h/mL. Similar dosing in dog resulted in significantly lower plasma levels (average AUC <2 microg h/mL). The 3-pyridylmethyl analog 30 gave the best overall exposure (rat AUC=7.1 microg h/mL and dog AUC=4.9 microg h/mL), however, this compound was found to be a potent inhibitor of cytochrome P450 3A (Ki=2.4 nM).

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Citations

Jun 19, 2013·Marine Drugs·Caroline B F Mourão, Elisabeth F Schwartz
Jul 1, 2008·Expert Opinion on Drug Discovery·Zhijian Lu
Jan 23, 2016·Journal of Medicinal Chemistry·Arun K GhoshGary Prato
Mar 2, 2011·Journal of Molecular Recognition : JMR·Helena C CastroCarlos R Rodrigues
Dec 29, 2007·Chemistry, an Asian Journal·Hisashi MiharaMasakatsu Shibasaki
Oct 16, 2016·Applied Microbiology and Biotechnology·Salwa Mansur AliNaveed Ahmed Khan
Jun 24, 2017·Chemical Reviews·Laure KonnertEvelina Colacino

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