Novel HIV-1 protease inhibitors active against multiple PI-resistant viral strains: coadministration with indinavir.
HIV-1 protease inhibitors (PI) with an N-arylpyrrole moiety in the P(3) position afforded excellent antiviral potency and substantially improved aqueous solubility over previously reported variants. The rapid in vitro clearance of these compounds in human liver microsomes prompted oral coadministration with indinavir to hinder their metabolism by the cyctochrome P450 3A4 isozyme and allow for in vivo PK assessment.
Kevin
Nancy J
NJ
Department of Basic Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA.
Duffy
Joseph L
JL
Kirk
Brian A
BA
Chapman
Kevin T
KT
Schleif
William A
WA
Olsen
David B
DB
Stahlhut
Mark
M
Rutkowski
Carrie A
CA
Kuo
Lawrence C
LC
Jin
Lixia
L
Lin
Jiunn H
JH
Emini
Emilio A
EA
Tata
James R
JR
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy; D000284:Administration, Oral; D001711:Biotransformation; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015195:Drug Design; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D016333:HIV Protease / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D019469:Indinavir / Q000494:pharmacology / Q000627:therapeutic use*; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D011758:Pyrroles / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship
D017320:HIV Protease Inhibitors; D011758:Pyrroles; D019469:Indinavir; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; D016333:HIV Protease