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  • Title: Synthesis, antiviral activity, and pharmacokinetic evaluation of P3 pyridylmethyl analogs of oximinoarylsulfonyl HIV-1 protease inhibitors.
    Author: Randolph JT, Huang PP, Flosi WJ, DeGoey D, Klein LL, Yeung CM, Flentge C, Sun M, Zhao C, Dekhtyar T, Mo H, Colletti L, Kati W, Marsh KC, Molla A, Kempf DJ.
    Journal: Bioorg Med Chem; 2006 Jun 15; 14(12):4035-46. PubMed ID: 16504523.
    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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