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 (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).
Randolph
John T
JT
Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA. john.randolph@abbott.com
Huang
Peggy P
PP
Flosi
William J
WJ
DeGoey
David
D
Klein
Larry L
LL
Yeung
Clinton M
CM
Flentge
Charles
C
Sun
Mingua
M
Zhao
Chen
C
Dekhtyar
Tatyana
T
Mo
Hongmei
H
Colletti
Lynn
L
Kati
Warren
W
Marsh
Kennan C
KC
Molla
Akhteruzzaman
A
Kempf
Dale J
DJ
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*
D019380:Anti-HIV Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D017320:HIV Protease Inhibitors; D011725:Pyridines; D013449:Sulfonamides