title: Synthesis, biological evaluation, and pharmacokinetic study of prolyl-1-piperazinylacetic acid and prolyl-4-piperidinylacetic acid derivatives as VLA-4 antagonists.
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).
authors.affiliation: Medicinal Chemistry Research Laboratory, Daiichi Pharmaceutical, Co., Ltd, 16-13, Kitakasai 1-chome, Tokyo 134-8630, Japan. chiba2mk@daiichipharm.co.jp
authors.forename: Jun
authors.initials: J
authors.lastname: Chiba
authors.forename: Gensuke
authors.initials: G
authors.lastname: Takayama
authors.forename: Tohru
authors.initials: T
authors.lastname: Takashi
authors.forename: Mika
authors.initials: M
authors.lastname: Yokoyama
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nakayama
authors.forename: John J
authors.initials: JJ
authors.lastname: Baldwin
authors.forename: Edward
authors.initials: E
authors.lastname: McDonald
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Moriarty
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Sarko
authors.forename: Kurt W
authors.initials: KW
authors.lastname: Saionz
authors.forename: Robert
authors.initials: R
authors.lastname: Swanson
authors.forename: Zahid
authors.initials: Z
authors.lastname: Hussain
authors.forename: Angela
authors.initials: A
authors.lastname: Wong
authors.forename: Nobuo
authors.initials: N
authors.lastname: Machinaga
mesh_terms: 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
chemical_list: D000085:Acetates; D039041:Integrin alpha4beta1; D010879:Piperazines; D010880:Piperidines; C511578:prolyl-1-piperazinylacetic acid; C511579:prolyl-4-piperidinylacetic acid; D011392:Proline