ABSTRACT
From a series of N-acyl 4-(3-pyridonyl)phenylalanine derivatives of 4, the trifluoromethyl derivative 28 was identified as a potent, dual acting alpha4 integrin antagonist with activity in primate models of allergic asthma. Investigation of a series of prodrug esters led to the discovery of the morpholinopropyl derivative 48 that demonstrated good intestinal fluid stability, solubility and permeability. Compound 48 gave high blood levels of 28 when dosed orally in cynomolgus monkeys. Surprisingly, hydrolysis of 48 was rapid in liver microsomes from the pharmacological species, mouse, rat and monkey, but slow in dog and human; in vivo studies also indicated there was prolonged exposure to unchanged prodrug in dogs.
Subject(s)
Integrin alpha4beta1/antagonists & inhibitors , Integrins/antagonists & inhibitors , Phenylalanine/analogs & derivatives , Animals , Dogs , Esters/blood , Esters/pharmacology , Humans , Mice , Phenylalanine/pharmacology , Prodrugs/chemistry , Prodrugs/pharmacology , RatsABSTRACT
A systematic structure-activity relationship investigation of the lead compound 1 resulted the identification of several N-[(substituted alkyl)cycloalkanoyl]-4-[((2,6-dichlorophenyl)carbonyl)amino]-L-phenylalanine derivatives as potent VCAM/VLA-4 antagonists. The data are consistent with a model of these compounds in which these alkanoylphenylalanines reside in a compact gauche (-) bioactive conformation.
Subject(s)
Integrin alpha4beta1/antagonists & inhibitors , Phenylalanine/analogs & derivatives , Vascular Cell Adhesion Molecule-1/drug effects , Crystallography, X-Ray , Cycloparaffins/chemical synthesis , Cycloparaffins/pharmacology , Humans , Inhibitory Concentration 50 , Molecular Structure , Phenylalanine/pharmacology , Protein Binding , Structure-Activity RelationshipABSTRACT
A series of N-benzoyl-4-[(2,6-dichlorobenzoyl)amino]-L-phenylalanine derivatives was prepared in order to optimize the substitution on the N-benzoyl moiety for VCAM/VLA-4 antagonist activity. Disubstitution in the 2- and 6-positions is favored and a range of small alkyl and halogen are tolerated. A model of the bioactive conformation of these compounds is proposed.
