TY - JOUR
T1 - Nonpeptidic HIV protease inhibitors possessing excellent antiviral activities and therapeutic indices. PD 178390
T2 - A lead HIV protease inhibitor
AU - Vara Prasad, J. V.N.
AU - Boyer, Frederick E.
AU - Domagala, John M.
AU - Ellsworth, Edmund L.
AU - Gajda, Christopher
AU - Hamilton, Harriet W.
AU - Hagen, Susan E.
AU - Markoski, Larry J.
AU - Steinbaugh, Bruce A.
AU - Tait, Bradley D.
AU - Humblet, Christine
AU - Lunney, Elizabeth A.
AU - Pavlovsky, Alexander
AU - Rubin, John R.
AU - Ferguson, Donna
AU - Graham, Neil
AU - Holler, Tod
AU - Hupe, Donald
AU - Nouhan, Carolyn
AU - Tummino, Peter J.
AU - Urumov, A.
AU - Zeikus, Eric
AU - Zeikus, Greg
AU - Gracheck, Stephen J.
AU - Saunders, James M.
AU - Vanderroest, Steven
AU - Brodfuehrer, Joanne
AU - Iyer, K.
AU - Sinz, M.
AU - Gulnik, Sergei V.
AU - Erickson, John W.
PY - 1999/12
Y1 - 1999/12
N2 - With the insight generated by the availability of X-ray crystal structures of various 5,6-dihydropyran-2-ones bound to HIV PR, inhibitors possessing various alkyl groups at the 6-position of 5,6-dihydropyran-2-one ring were synthesized. The inhibitors possessing a 6-alkyl group exhibited superior antiviral activities when compared to 6-phenyl analogues. Antiviral efficacies were further improved upon introduction of a polar group (hydroxyl or amino) on the 4-position of the phenethyl moiety as well as the polar group (hydroxymethyl) on the 3-(tert-butyl-5-methyl-phenylthio) moiety. The polar substitution is also advantageous for decreasing toxicity, providing inhibitors with higher therapeutic indices. The best inhibitor among this series, (S)-6-[2-(4-aminophenyl)-ethyl]-(3-(2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one (34S), exhibited an EC50 of 200 nM with a therapeutic index of >1000. More importantly, these non-peptidic inhibitors, 16S and 34S, appear to offer little cross-resistance to the currently marketed peptidomimetic PR inhibitors. The selected inhibitors tested in vitro against mutant HIV PR showed a very small increase in binding affinities relative to wild-type HIV PR. C(max) and absolute bioavailability of 34S were higher and half-life and time above EC95 were longer compared to 16S. Thus 34S, also known as PD 178390, which displays good antiviral efficacy, promising pharmacokinetic characteristics and favorable activity against mutant enzymes and CYP3A4, has been chosen for further preclinical evaluation. Copyright (C) 1999 Elsevier Science Ltd.
AB - With the insight generated by the availability of X-ray crystal structures of various 5,6-dihydropyran-2-ones bound to HIV PR, inhibitors possessing various alkyl groups at the 6-position of 5,6-dihydropyran-2-one ring were synthesized. The inhibitors possessing a 6-alkyl group exhibited superior antiviral activities when compared to 6-phenyl analogues. Antiviral efficacies were further improved upon introduction of a polar group (hydroxyl or amino) on the 4-position of the phenethyl moiety as well as the polar group (hydroxymethyl) on the 3-(tert-butyl-5-methyl-phenylthio) moiety. The polar substitution is also advantageous for decreasing toxicity, providing inhibitors with higher therapeutic indices. The best inhibitor among this series, (S)-6-[2-(4-aminophenyl)-ethyl]-(3-(2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one (34S), exhibited an EC50 of 200 nM with a therapeutic index of >1000. More importantly, these non-peptidic inhibitors, 16S and 34S, appear to offer little cross-resistance to the currently marketed peptidomimetic PR inhibitors. The selected inhibitors tested in vitro against mutant HIV PR showed a very small increase in binding affinities relative to wild-type HIV PR. C(max) and absolute bioavailability of 34S were higher and half-life and time above EC95 were longer compared to 16S. Thus 34S, also known as PD 178390, which displays good antiviral efficacy, promising pharmacokinetic characteristics and favorable activity against mutant enzymes and CYP3A4, has been chosen for further preclinical evaluation. Copyright (C) 1999 Elsevier Science Ltd.
KW - Anti-HIV agents
KW - Antivirals
KW - Aspartic protease inhibitors
KW - HIV protease inhibitors
KW - Nonpeptidic HIV protease inhibitors
UR - http://www.scopus.com/inward/record.url?scp=0033391195&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0033391195&partnerID=8YFLogxK
U2 - 10.1016/S0968-0896(99)00215-1
DO - 10.1016/S0968-0896(99)00215-1
M3 - Article
C2 - 10658583
AN - SCOPUS:0033391195
SN - 0968-0896
VL - 7
SP - 2775
EP - 2800
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 12
ER -