title: HIV-1 protease inhibitors with picomolar potency against PI-resistant HIV-1 by modification of the P1' substituent.
abstract: Transposition of the pyridyl nitrogen from the P(3) substituent to the P(1)' substituent in HIV-1 protease inhibitors (PI) affords compounds such as 3 with an improved inhibitory profile against multiple P450 isoforms. These compounds also displayed increased potency, with 3 inhibiting viral spread (CIC(95)) at <8 nM for every strain of PI-resistant HIV-1 tested. The poor to modest bioavailability of these compounds may correlate in part to their aqueous solubility.
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: Brian A
authors.initials: BA
authors.lastname: Kirk
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; D004285:Dogs; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000502:physiology; D016333:HIV Protease / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000737:chemistry*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology*; D006801:Humans
chemical_list: D017320:HIV Protease Inhibitors; D016333:HIV Protease