title: Synthesis, antiviral activity, and pharmacokinetic evaluation of P3 pyridylmethyl analogs of oximinoarylsulfonyl HIV-1 protease inhibitors.
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).
authors.affiliation: Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA. john.randolph@abbott.com
authors.forename: John T
authors.initials: JT
authors.lastname: Randolph
authors.forename: Peggy P
authors.initials: PP
authors.lastname: Huang
authors.forename: William J
authors.initials: WJ
authors.lastname: Flosi
authors.forename: David
authors.initials: D
authors.lastname: DeGoey
authors.forename: Larry L
authors.initials: LL
authors.lastname: Klein
authors.forename: Clinton M
authors.initials: CM
authors.lastname: Yeung
authors.forename: Charles
authors.initials: C
authors.lastname: Flentge
authors.forename: Mingua
authors.initials: M
authors.lastname: Sun
authors.forename: Chen
authors.initials: C
authors.lastname: Zhao
authors.forename: Tatyana
authors.initials: T
authors.lastname: Dekhtyar
authors.forename: Hongmei
authors.initials: H
authors.lastname: Mo
authors.forename: Lynn
authors.initials: L
authors.lastname: Colletti
authors.forename: Warren
authors.initials: W
authors.lastname: Kati
authors.forename: Kennan C
authors.initials: KC
authors.lastname: Marsh
authors.forename: Akhteruzzaman
authors.initials: A
authors.lastname: Molla
authors.forename: Dale J
authors.initials: DJ
authors.lastname: Kempf
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D019540:Area Under Curve; D065692:Cytochrome P-450 CYP3A Inhibitors; D004285:Dogs; D015195:Drug Design; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D011725:Pyridines / Q000737:chemistry; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D017320:HIV Protease Inhibitors; D011725:Pyridines; D013449:Sulfonamides