Structure-activity relationship of small-sized HIV protease inhibitors containing allophenylnorstatine

T Mimoto; R Kato; H Takaku; S Nojima; K Terashima; S Misawa; T Fukazawa; T Ueno; H Sato; M Shintani; Y Kiso; H Hayashi

doi:10.1021/jm980637h

Structure-activity relationship of small-sized HIV protease inhibitors containing allophenylnorstatine

J Med Chem. 1999 May 20;42(10):1789-802. doi: 10.1021/jm980637h.

Authors

T Mimoto¹, R Kato, H Takaku, S Nojima, K Terashima, S Misawa, T Fukazawa, T Ueno, H Sato, M Shintani, Y Kiso, H Hayashi

Affiliation

¹ Pharmaceuticals & Biotechnology Laboratory, Japan Energy Corporation, Toda-shi, Saitama 335-8502, Japan.

PMID: 10346931
DOI: 10.1021/jm980637h

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

Administration, Oral
Animals
Biological Availability
Cell Line
Dipeptides / chemical synthesis*
Dipeptides / chemistry
Dipeptides / pharmacokinetics
Dipeptides / pharmacology
Dogs
Drug Evaluation, Preclinical
HIV Protease Inhibitors / chemical synthesis*
HIV Protease Inhibitors / chemistry
HIV Protease Inhibitors / pharmacokinetics
HIV Protease Inhibitors / pharmacology
HIV-1 / enzymology
Inhibitory Concentration 50
Injections, Intravenous
Oligopeptides / chemical synthesis*
Oligopeptides / chemistry
Oligopeptides / pharmacokinetics
Oligopeptides / pharmacology
Phenylbutyrates / chemistry*
Rats
Structure-Activity Relationship
Thiazoles / chemical synthesis*
Thiazoles / chemistry
Thiazoles / pharmacokinetics
Thiazoles / pharmacology
Thiazolidines

Substances

Dipeptides
HIV Protease Inhibitors
N-(2-methylbenzyl)-3-(2-hydroxy-3-(3-hydroxy-2-methylbenzoyl)amino-4-phenylbutanoyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxamide
Oligopeptides
Phenylbutyrates
Thiazoles
Thiazolidines
3-amino-2-hydroxy-4-phenylbutanoic acid