Title of article :
Synthesis, biological evaluation, and pharmacokinetic study of prolyl-1-piperazinylacetic acid and prolyl-4-piperidinylacetic acid derivatives as VLA-4 antagonists Original Research Article
Author/Authors :
Jun Chiba، نويسنده , , Gensuke Takayama، نويسنده , , Tohru Takashi، نويسنده , , Mika Yokoyama، نويسنده , , Atsushi Nakayama، نويسنده , , John J. Baldwin، نويسنده , , B. Edward McDonald and William L. Siegmann، نويسنده , , Kevin J. Moriarty، نويسنده , , Christopher R. Sarko، نويسنده , , Kurt W. Saionz، نويسنده , , Robert Swanson، نويسنده , , Zahid Hussain، نويسنده , , Angela Wong، نويسنده , , Nobuo Machinaga، نويسنده ,
Abstract :
A series of prolyl-1-piperazinylacetic acid and prolyl-4-piperidinylacetic acid derivatives were synthesized and evaluated for their activity as VLA-4 antagonists. Of 22 compounds synthesized, 19 compounds showed potent activity with low nanomolar IC50 values. In addition, the representative compounds 11o and 11p with a hydroxy group in the pyrrolidine ring showed moderate plasma clearance in rats (11o, 30 ml/min/kg and 11p, 21 ml/min/kg) and in dogs (11o, 12 ml/min/kg and 11p, 9 ml/min/kg).
