Abstract
We designed and synthesized a new class of peptidomimetic human immunodeficiency virus (HIV) protease inhibitors containing a unique unnatural amino acid, allophenylnorstatine [Apns; (2S, 3S)-3-amino-2-hydroxy-4-phenylbutyric acid], with a hydroxymethylcarbonyl (HMC) isostere as the active moiety. A systematic evaluation of structure-activity relationships for HIV protease inhibition, anti-HIV activities, and pharmacokinetic profiles has led to the delineation of a set of structural charateristics that appear to afford an orally available HIV protease inhibitor. Optimum structures, exemplified by 21f (JE-2147), incorporated 3-hydroxy-2-methylbenzoyl groups as the P2 ligand, (R)-5,5-dimethyl-1,3-thiazolidine-4-carbonyl (Dmt) residue at the P1' site, and 2-methylbenzylcarboxamide group as the P2' ligand. The present study demonstrated that JE-2147 has potent antiviral activities in vitro and exhibits good oral bioavailability and plasma pharmacokinetic profiles in two species of laboratory animals.
MeSH terms
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Administration, Oral
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Animals
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Biological Availability
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Cell Line
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Dipeptides / chemical synthesis*
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Dipeptides / chemistry
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Dipeptides / pharmacokinetics
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Dipeptides / pharmacology
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Dogs
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Drug Evaluation, Preclinical
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HIV Protease Inhibitors / chemical synthesis*
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HIV Protease Inhibitors / chemistry
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HIV Protease Inhibitors / pharmacokinetics
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HIV Protease Inhibitors / pharmacology
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HIV-1 / enzymology
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Inhibitory Concentration 50
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Injections, Intravenous
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Oligopeptides / chemical synthesis*
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Oligopeptides / chemistry
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Oligopeptides / pharmacokinetics
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Oligopeptides / pharmacology
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Phenylbutyrates / chemistry*
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Rats
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Structure-Activity Relationship
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Thiazoles / chemical synthesis*
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Thiazoles / chemistry
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Thiazoles / pharmacokinetics
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Thiazoles / pharmacology
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Thiazolidines
Substances
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Dipeptides
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HIV Protease Inhibitors
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N-(2-methylbenzyl)-3-(2-hydroxy-3-(3-hydroxy-2-methylbenzoyl)amino-4-phenylbutanoyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxamide
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Oligopeptides
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Phenylbutyrates
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Thiazoles
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Thiazolidines
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3-amino-2-hydroxy-4-phenylbutanoic acid