Symmetry-based inhibitors of HIV protease. Structure-activity studies of acylated 2,4-diamino-1,5-diphenyl-3-hydroxypentane and 2,5-diamino-1,6-diphenylhexane-3,4-diol

The structure-activity relationships in two series of novel, symmetry-based inhibitors of HIV protease, the enzyme responsible for maturation of the human immunodeficiency virus, are described. Beginning with lead compounds 3-6, the effect of adding polar, heterocyclic end groups to one or both ends...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1993-02, Vol.36 (3), p.320-330
Main Authors: Kempf, Dale J, Codacovi, Lynnmarie, Wang, Xiu Chun, Kohlbrenner, William E, Wideburg, Norman E, Saldivar, Ayda, Vasavanonda, Sudthida, Marsh, Kennan C, Bryant, Pamela
Format: Article
Language:English
Subjects:
AIDS/HIV
Aliphatic compounds
Amino Alcohols - chemistry
Amino Alcohols - pharmacology
Chemical Phenomena
Chemistry
Chemistry, Physical
Cytopathogenic Effect, Viral - drug effects
Diamines - chemistry
Diamines - pharmacology
Exact sciences and technology
HIV Protease Inhibitors - chemistry
HIV Protease Inhibitors - pharmacology
HIV-1 - drug effects
HIV-1 - enzymology
human immunodeficiency virus 1
Molecular Structure
Organic chemistry
Preparations and properties
Structure-Activity Relationship
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Summary:The structure-activity relationships in two series of novel, symmetry-based inhibitors of HIV protease, the enzyme responsible for maturation of the human immunodeficiency virus, are described. Beginning with lead compounds 3-6, the effect of adding polar, heterocyclic end groups to one or both ends of the symmetric or pseudosymmetric inhibitors was probed. Aqueous solubility was enhanced > 1000-fold while maintaining potent inhibition of purified HIV-1 protease and anti-HIV activity in vitro. Pharmacokinetic studies in rats indicated a substantial difference in the absorption properties of mono-ol-based and diol-based inhibitors. The oral bioavailability of inhibitor 19 in rats was 19%; however, the Cmax obtained failed to exceed the anti-HIV EC50 in vitro. Substantial plasma levels of potent inhibitors of the diol class were not obtained after oral administration in rats; however, the optimal combination of aqueous solubility and in vitro antiviral activity of several inhibitors support their potential use in intravenous therapy.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00055a003