ABSTRACT
We describe a series of dehydrophenylalanine derivatives where the Z isomers are potent VLA-4 antagonists but are subject to rapid biliary clearance and the E isomers have poor activity but have a slower rate of clearance. These configurationally constrained molecules have led to the design of a novel class of benzodiazepine VLA-4 antagonists.
Subject(s)
Integrin alpha4beta1/antagonists & inhibitors , Phenylalanine/analogs & derivatives , Phenylalanine/chemistry , Phenylalanine/pharmacology , Animals , Benzodiazepines/chemistry , Benzodiazepines/pharmacology , Biliary Tract/metabolism , Drug Design , Inhibitory Concentration 50 , Isomerism , Phenylalanine/pharmacokinetics , Rats , Structure-Activity RelationshipABSTRACT
SAR studies aimed at improving the rate of clearance of a series of VLA-4 integrin antagonists by the introduction of a 1,3,5-triazine as an amide isostere are described.
Subject(s)
Integrin alpha4beta1/antagonists & inhibitors , Phenylalanine/chemistry , Phenylalanine/pharmacology , Triazines/chemistry , Triazines/pharmacology , Phenylalanine/analogs & derivatives , Structure-Activity RelationshipABSTRACT
The SAR studies to optimise both potency and rate of clearance in the rat for a series of pyrimidine and pyridine based VLA-4 antagonists are described.
Subject(s)
Integrin alpha4beta1/antagonists & inhibitors , Phenylalanine/chemistry , Phenylalanine/pharmacology , Pyridines/chemistry , Pyridines/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Phenylalanine/analogs & derivatives , Structure-Activity RelationshipABSTRACT
SAR studies aimed at improving the rate of clearance by the incorporation of a 3,4-diamino-3-cyclobutene-1,2-dione group as an amino acid isostere in a series of VLA-4 integrin antagonists are described.