ABSTRACT
A series of potent α4ß1/α4ß7 integrin inhibitors is reported, including an inhibitor 12d with remarkable oral exposure and efficacy in rat models of rheumatoid arthritis and Crohn's disease.
Subject(s)
Integrin alpha4beta1/antagonists & inhibitors , Integrins/antagonists & inhibitors , Administration, Oral , Animals , Area Under Curve , Arthritis, Rheumatoid/chemically induced , Arthritis, Rheumatoid/drug therapy , Crohn Disease/drug therapy , Disease Models, Animal , Half-Life , Humans , Integrin alpha4beta1/metabolism , Integrins/metabolism , Jurkat Cells , Microsomes, Liver/metabolism , RatsABSTRACT
Mitsunobu reactions were employed to link t-butyl esters of α4 integrin inhibitors at each of the termini of a three-arm, 40 kDa, branched PEG. Cleavage of the t-butyl esters using HCO2H provided easily isolated PEG derivatives, which are potent α4 integrin inhibitors, and which achieve sustained levels and bioactivity in vivo, following subcutaneous administration to rats.
Subject(s)
Integrin alpha4/chemistry , Polyethylene Glycols/chemistry , Animals , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/pharmacokinetics , Esters , Half-Life , Humans , Injections, Subcutaneous , Integrin alpha4/immunology , Integrin alpha4/metabolism , Jurkat Cells , RatsABSTRACT
A series of N-(pyrimidin-4-yl)-phenylalanine VLA-4 antagonists is described. Optimization of substituents at the 2 and 5 positions of the pyrimidine ring gave 14, a very potent VLA-4 inhibitor which is orally active in a sheep asthma model.