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

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• 作者：John T. Randolph ; Peggy P. Huang ; William J. Flosi ; David DeGoey ; Larry L. Klein ; Clinton M. Yeung ; Charles Flentge ; Mingua Sun ; Chen Zhao ; Tatyana Dekhtyar et al.
• 关键词：HIV ; Aspartyl protease inhibitors ; Lopinavir resistant virus ; Peptidomimetic
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2006
• 出版时间：15 June 2006
• 年：2006
• 卷：14
• 期：12
• 页码：4035-4046
• 全文大小：268 K

文摘

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 (K_i = 2.4 nM).