ABSTRACT
A novel series of pyridazinone-functionalized phenylalanine analogues was prepared and evaluated for inhibition of cellular adhesion mediated by alpha4beta1/VCAM-1 and alpha4beta7/MAdCAM-1 interactions. Concise syntheses were developed and applied for exploration of structure-activity relationships pertaining to the pyridazinone ring as well as the N-acyl phenylalanine scaffold. Potent dual antagonists of alpha4beta1 and alpha4beta7 were generated from an amide subseries; antagonists selective for alpha4beta7 were identified from urea and carbamate-based subseries. The pharmacokinetic properties of selected members of the series have been determined in rats and demonstrate that the use of ester prodrugs and alterations to the amide linkage can lead to improved oral bioavailability in this series. An alpha4beta7-selective member of the carbamate subseries (36c), upon oral administration, demonstrated in vivo efficacy in the mouse DSS colitis model.
Subject(s)
Integrin alpha4beta1/antagonists & inhibitors , Integrins/antagonists & inhibitors , Phenylalanine/analogs & derivatives , Pyridazines/chemical synthesis , Animals , Biological Availability , Cell Adhesion/drug effects , Cell Adhesion Molecules , Colitis/chemically induced , Colitis/drug therapy , Dextran Sulfate , Endothelial Cells/drug effects , Endothelial Cells/physiology , Esters/chemical synthesis , Esters/chemistry , Esters/pharmacology , Granulocytes/drug effects , Granulocytes/physiology , Humans , Immunoglobulins/metabolism , In Vitro Techniques , Integrin alpha4beta1/metabolism , Integrins/metabolism , K562 Cells , Lymphocytes/drug effects , Lymphocytes/physiology , Mice , Monocytes/drug effects , Monocytes/physiology , Mucoproteins/metabolism , Phenylalanine/chemical synthesis , Phenylalanine/chemistry , Phenylalanine/pharmacology , Prodrugs/chemical synthesis , Prodrugs/chemistry , Prodrugs/pharmacology , Pyridazines/chemistry , Pyridazines/pharmacology , Rats , Structure-Activity Relationship , Umbilical Veins/cytology , Vascular Cell Adhesion Molecule-1/metabolismABSTRACT
Reduction of the quinoline ring in an alpha(v)beta(3) antagonist yielded a 1,2,3,4-tetrahydro derivative as two diastereomers, the four isomers of which were separated by sequential chiral HPLC. Two isomers had significant alpha(V)beta(3) antagonist activity with improved oral bioavailability, relative to the corresponding quinoline derivative.
