title: Identified a morpholinyl-4-piperidinylacetic acid derivative as a potent oral active VLA-4 antagonist.
abstract: An investigation into the structure-activity relationship of a lead compound, prolyl-5-aminopentanoic acid 4, led to the identification of a novel series of 4-piperidinylacetic acid, 1-piperazinylacetic acid, and 4-aminobenzoic acid derivatives as potent VLA-4 antagonists with low nanomolar IC(50) values. A representative compound morpholinyl-4-piperidinylacetic acid derivative (13d: IC(50)=4.4 nM) showed efficacy in the Ascaris-antigen sensitized murine airway inflammation model by oral administration.
authors.affiliation: Medicinal Chemistry Research Laboratory, Daiichi Pharmaceutical Co. Ltd, 16-13 Kitakasai 1-chome, Edogawa-ku, Tokyo 134-8630, Japan. chiba2mk@daiichipharm.co.jp
authors.forename: Jun
authors.initials: J
authors.lastname: Chiba
authors.forename: Nobuo
authors.initials: N
authors.lastname: Machinaga
authors.forename: Tohru
authors.initials: T
authors.lastname: Takashi
authors.forename: Akio
authors.initials: A
authors.lastname: Ejima
authors.forename: Gensuke
authors.initials: G
authors.lastname: Takayama
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
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001249:Asthma / Q000209:etiology / Q000378:metabolism; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D051379:Mice; D009025:Morpholines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D010880:Piperidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D039041:Integrin alpha4beta1; D009025:Morpholines; D010880:Piperidines; C500014:morpholinyl-4-piperidinylacetic acid