HIV protease inhibitors with picomolar potency against PI-Resistant HIV-1 by extension of the P3 substituent.
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.
Duffy
Joseph L
JL
Department of Basic Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. joseph_duffy@merck.com
Rano
Thomas A
TA
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; 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
D065607:Cytochrome P-450 Enzyme Inhibitors; D017320:HIV Protease Inhibitors; D007527:Isoenzymes; D019469:Indinavir