title: Nonpeptidic HIV protease inhibitors possessing excellent antiviral activities and therapeutic indices. PD 178390: a lead HIV protease inhibitor.
abstract: 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-phenylsulfa nyl)-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. Cmax 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.
authors.affiliation: Department of Chemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, MI 48105, USA. varaprj@aa.wl.com
authors.forename: J V
authors.initials: JV
authors.lastname: Prasad
authors.forename: F E
authors.initials: FE
authors.lastname: Boyer
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authors.initials: JM
authors.lastname: Domagala
authors.forename: E L
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authors.lastname: Ellsworth
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authors.lastname: Hamilton
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authors.lastname: Hagen
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authors.initials: LJ
authors.lastname: Markoski
authors.forename: B A
authors.initials: BA
authors.lastname: Steinbaugh
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authors.initials: BD
authors.lastname: Tait
authors.forename: C
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authors.lastname: Humblet
authors.forename: E A
authors.initials: EA
authors.lastname: Lunney
authors.forename: A
authors.initials: A
authors.lastname: Pavlovsky
authors.forename: J R
authors.initials: JR
authors.lastname: Rubin
authors.forename: D
authors.initials: D
authors.lastname: Ferguson
authors.forename: N
authors.initials: N
authors.lastname: Graham
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authors.lastname: Holler
authors.forename: D
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authors.lastname: Hupe
authors.forename: C
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authors.lastname: Nouhan
authors.forename: P J
authors.initials: PJ
authors.lastname: Tummino
authors.forename: A
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authors.lastname: Urumov
authors.forename: E
authors.initials: E
authors.lastname: Zeikus
authors.forename: G
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authors.lastname: Zeikus
authors.forename: S J
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authors.lastname: Erickson
mesh_terms: D002460:Cell Line; D018360:Crystallography, X-Ray; D065607:Cytochrome P-450 Enzyme Inhibitors; D004220:Disulfides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D016333:HIV Protease / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015497:HIV-1 / Q000201:enzymology / Q000235:genetics; D006801:Humans; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009154:Mutation; D011753:Pyrones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004220:Disulfides; D017320:HIV Protease Inhibitors; C400303:PD 178390; D011753:Pyrones; D016333:HIV Protease