title: The design, synthesis and evaluation of novel HIV-1 protease inhibitors with high potency against PI-resistant viral strains.
abstract: 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.
authors.affiliation: Department of Basic Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. abe_zhang@merck.com
authors.forename: Fengqi
authors.initials: F
authors.lastname: Zhang
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Chapman
authors.forename: William A
authors.initials: WA
authors.lastname: Schleif
authors.forename: David B
authors.initials: DB
authors.lastname: Olsen
authors.forename: Mark
authors.initials: M
authors.lastname: Stahlhut
authors.forename: Carrie A
authors.initials: CA
authors.lastname: Rutkowski
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Kuo
authors.forename: Lixia
authors.initials: L
authors.lastname: Jin
authors.forename: Jiunn H
authors.initials: JH
authors.lastname: Lin
authors.forename: Emilio A
authors.initials: EA
authors.lastname: Emini
authors.forename: James R
authors.initials: JR
authors.lastname: Tata
mesh_terms: 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
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D017320:HIV Protease Inhibitors; D019469:Indinavir; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A