Structure-activity relationship of small-sized HIV protease inhibitors containing allophenylnorstatine.
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.
Mimoto
T
T
Pharmaceuticals & Biotechnology Laboratory, Japan Energy Corporation, Toda-shi, Saitama 335-8502, Japan.
Kato
R
R
Takaku
H
H
Nojima
S
S
Terashima
K
K
Misawa
S
S
Fukazawa
T
T
Ueno
T
T
Sato
H
H
Shintani
M
M
Kiso
Y
Y
Hayashi
H
H
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002460:Cell Line; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D015497:HIV-1 / Q000201:enzymology; D020128:Inhibitory Concentration 50; D007275:Injections, Intravenous; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D010654:Phenylbutyrates / Q000737:chemistry*; D051381:Rats; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D053778:Thiazolidines
D004151:Dipeptides; D017320:HIV Protease Inhibitors; C119213:N-(2-methylbenzyl)-3-(2-hydroxy-3-(3-hydroxy-2-methylbenzoyl)amino-4-phenylbutanoyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxamide; D009842:Oligopeptides; D010654:Phenylbutyrates; D013844:Thiazoles; D053778:Thiazolidines; C034940:3-amino-2-hydroxy-4-phenylbutanoic acid