title: HIV protease inhibitors with picomolar potency against PI-Resistant HIV-1 by extension of the P3 substituent.
abstract: A biaryl pyridylfuran P(3) substituent on the hydroxyethylene isostere scaffold affords HIV protease inhibitors (PI's) with picomolar (IC(50)) potency against the protease enzymes from PI-resistant HIV-1 strains. Inclusion of a gem-dimethyl substituent afforded compound 3 with 100% oral bioavailability (dogs) and more than double the t(1/2) of indinavir. Inhibition of multiple P450 isoforms is dependent on the regiochemistry of the pyridyl nitrogen in these compounds.
authors.affiliation: Department of Basic Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. joseph_duffy@merck.com
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Duffy
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Rano
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Kevin
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; 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; D006207:Half-Life; D019469:Indinavir / Q000493:pharmacokinetics; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008253:Macaca mulatta; D009154:Mutation / Q000235:genetics; D013329:Structure-Activity Relationship
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D017320:HIV Protease Inhibitors; D007527:Isoenzymes; D019469:Indinavir