Synthesis, biological evaluation, and pharmacokinetic study of prolyl-1-piperazinylacetic acid and prolyl-4-piperidinylacetic acid derivatives as VLA-4 antagonists.
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).
Chiba
Jun
J
Medicinal Chemistry Research Laboratory, Daiichi Pharmaceutical, Co., Ltd, 16-13, Kitakasai 1-chome, Tokyo 134-8630, Japan. chiba2mk@daiichipharm.co.jp
Takayama
Gensuke
G
Takashi
Tohru
T
Yokoyama
Mika
M
Nakayama
Atsushi
A
Baldwin
John J
JJ
McDonald
Edward
E
Moriarty
Kevin J
KJ
Sarko
Christopher R
CR
Saionz
Kurt W
KW
Swanson
Robert
R
Hussain
Zahid
Z
Wong
Angela
A
Machinaga
Nobuo
N
D000085:Acetates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D004285:Dogs; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D010879:Piperazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011392:Proline / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016339:Spectrometry, Mass, Fast Atom Bombardment
D000085:Acetates; D039041:Integrin alpha4beta1; D010879:Piperazines; D010880:Piperidines; C511578:prolyl-1-piperazinylacetic acid; C511579:prolyl-4-piperidinylacetic acid; D011392:Proline