HIV-1 protease inhibitors with picomolar potency against PI-resistant HIV-1 by modification of the P1' substituent.
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.
Duffy
Joseph L
JL
Department of Basic Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. joseph_duffy@merck.com
Kirk
Brian A
BA
Kevin
Nancy J
NJ
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; 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
D017320:HIV Protease Inhibitors; D016333:HIV Protease