The design, synthesis and evaluation of novel HIV-1 protease inhibitors with high potency against PI-resistant viral strains.
Replacement of the pyridylmethyl moiety in indinavir with a pyridyl oxazole yielded HIV-1 protease inhibitors (PI) with greatly improved potency against PI-resistant HIV-1 strains. A meta-methoxy group on the pyridyl ring and a gem-dimethyl methyl linkage afforded compound 10 with notable in vitro antiviral activity against HIV-1 viral strains with reduced susceptibility to the clinically available PIs. Compound 10 also demonstrated favorable in vivo pharmacokinetics in animal models.
Zhang
Fengqi
F
Department of Basic Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. abe_zhang@merck.com
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
D000818:Animals; D001682:Biological Availability; D002460:Cell Line; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004285:Dogs; D024882:Drug Resistance, Viral; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D066298:In Vitro Techniques; D019469:Indinavir / Q000493:pharmacokinetics / Q000494:pharmacology; D008253:Macaca mulatta; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D013601:T-Lymphocytes / Q000187:drug effects / Q000821:virology
D065607:Cytochrome P-450 Enzyme Inhibitors; D017320:HIV Protease Inhibitors; D019469:Indinavir; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A