title: Isoxazolyl, oxazolyl, and thiazolylpropionic acid derivatives as potent alpha(4)beta(1) integrin antagonists.
abstract: A series of isoxazolyl, oxazolyl, and thiazolylpropionic acid derivatives derived from LDV was found to be a potent antagonist of the alpha(4)beta(1) integrin. The synthesis and SAR leading up to 3-[3-(1-[-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino]-3-methyl-butyl)-isoxazol-5-yl]-propionic acid (22) are reported. In an allergic mouse model, compound 22 was efficacious delivered systemically (58% inhib @ 10 mg/kg, sc) as well as by intra-tracheal instillation (ED(50)=2 microg/kg).
authors.affiliation: Pfizer Global Research and Development, Groton Labs, Eastern Point Road, Groton, CT 06340, USA. allen_j_duplantier@groton.pfizer.com
authors.forename: A J
authors.initials: AJ
authors.lastname: Duplantier
authors.forename: G E
authors.initials: GE
authors.lastname: Beckius
authors.forename: R J
authors.initials: RJ
authors.lastname: Chambers
authors.forename: L S
authors.initials: LS
authors.lastname: Chupak
authors.forename: T H
authors.initials: TH
authors.lastname: Jenkinson
authors.forename: A S
authors.initials: AS
authors.lastname: Klein
authors.forename: K G
authors.initials: KG
authors.lastname: Kraus
authors.forename: E M
authors.initials: EM
authors.lastname: Kudlacz
authors.forename: M W
authors.initials: MW
authors.lastname: McKechney
authors.forename: M P
authors.initials: MP
authors.lastname: Pettersson
authors.forename: C A
authors.initials: CA
authors.lastname: Whitney
authors.forename: A J
authors.initials: AJ
authors.lastname: Milici
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D006967:Hypersensitivity / Q000188:drug therapy; D039041:Integrin alpha4beta1; D016023:Integrins / Q000037:antagonists & inhibitors*; D007555:Isoxazoles / Q000494:pharmacology*; D019169:Jurkat Cells; D051379:Mice; D011422:Propionates / Q000494:pharmacology*; D016201:Receptors, Lymphocyte Homing / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: C439163:3-(3-(1-(-(3-methoxy-4-(3-o-tolyl-ureido)-phenyl)-acetylamino)-3-methyl-butyl)-isoxazol-5-yl)-propionic acid; D039041:Integrin alpha4beta1; D016023:Integrins; D007555:Isoxazoles; D011422:Propionates; D016201:Receptors, Lymphocyte Homing