1.
Bioorg Med Chem Lett
; 8(20): 2907-12, 1998 Oct 20.
Article
in English
| MEDLINE
| ID: mdl-9873646
ABSTRACT
Kynurenine 3-hydroxylase (KYN 3-OHase) is a key enzyme in the kynurenine pathway of tryptophan degradation and its inhibition may be an effective mechanism for counteracting neuronal excitotoxic damage. We present here a new class of inhibitors derived from a structure-activity relationship (SAR) study of the benzoylalanine side-chain of 1. 2-hydroxy-4-(3,4-dichlorophenyl)-4-oxobutanoic acid (8) and 2-benzyl-4-(3,4-dichlorophenyl)-4-oxo-butanoic acid (10) emerged as the most interesting derivatives. Enantiospecific synthesis for both enantiomers of 8 and diastereomeric salt resolution for those of 10 were successfully applied.
Subject(s)
Enzyme Inhibitors/chemistry , Mixed Function Oxygenases/antagonists & inhibitors , Phenylbutyrates/chemistry , Animals , Brain/drug effects , Brain/enzymology , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Kynurenine 3-Monooxygenase , Liver/drug effects , Liver/enzymology , Phenylbutyrates/pharmacology , Rats , Structure-Activity Relationship , Tryptophan/metabolism
2.
Adv Exp Med Biol
; 398: 531-4, 1996.
Article
in English
| MEDLINE
| ID: mdl-8906317
Subject(s)
Alanine/analogs & derivatives , Alanine/chemical synthesis , Benzoates/chemical synthesis , Brain/enzymology , Enzyme Inhibitors/chemical synthesis , Hydrolases/antagonists & inhibitors , Mixed Function Oxygenases/antagonists & inhibitors , Alanine/chemistry , Alanine/pharmacology , Animals , Benzoates/chemistry , Benzoates/pharmacology , Drug Design , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Indicators and Reagents , Kinetics , Kynurenine 3-Monooxygenase , Male , Rats , Rats, Wistar , Stereoisomerism , Structure-Activity Relationship
3.
Adv Exp Med Biol
; 398: 535-8, 1996.
Article
in English
| MEDLINE
| ID: mdl-8906318