title: Aza-bicyclic amino acid sulfonamides as alpha(4)beta(1)/alpha(4)beta(7) integrin antagonists.
abstract: The design, synthesis, and biological activity of novel alpha(4)beta(1) and alpha(4)beta(7) integrin antagonists, containing a bridged azabicyclic nucleus, are reported. Conformational analysis of targets containing an azabicyclo[2.2.2]octane carboxylic acid and known integrin antagonists indicated that this azabicycle would be a suitable molecular scaffold. Variation of substituents on the pendant arylsulfonamide and phenylalanine groups resulted in potent alpha(4)beta(1)-selective and dual alpha(4)beta(1)/alpha(4)beta(7) antagonists. Potent compounds 11i, 11h, and 14 were effective in the antigen-sensitized sheep model of asthma.
authors.affiliation: Drug Discovery, Johnson & Johnson Pharmaceutical Research & Development, LLC, Spring House, PA 19477-0776, USA. adyatkin@prdus.jnj.com
authors.forename: Alexey B
authors.initials: AB
authors.lastname: Dyatkin
authors.forename: William J
authors.initials: WJ
authors.lastname: Hoekstra
authors.forename: William A
authors.initials: WA
authors.lastname: Kinney
authors.forename: Maria
authors.initials: M
authors.lastname: Kontoyianni
authors.forename: Rosemary J
authors.initials: RJ
authors.lastname: Santulli
authors.forename: Edward S
authors.initials: ES
authors.lastname: Kimball
authors.forename: M Carolyn
authors.initials: MC
authors.lastname: Fisher
authors.forename: M
authors.initials: M
authors.lastname: Carolyn Fisher
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Prouty
authors.forename: William M
authors.initials: WM
authors.lastname: Abraham
authors.forename: Lawrence
authors.initials: L
authors.lastname: de Garavilla
authors.forename: Patricia
authors.initials: P
authors.lastname: Andrade-Gordon
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Hlasta
authors.forename: Wei
authors.initials: W
authors.lastname: He
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Hornby
authors.forename: Bruce P
authors.initials: BP
authors.lastname: Damiano
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Maryanoff
mesh_terms: D000596:Amino Acids; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000947:Antigens, Helminth / Q000276:immunology*; D001200:Ascaris / Q000276:immunology; D001249:Asthma / Q000188:drug therapy / Q000473:pathology; D001372:Aza Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001980:Bronchi / Q000276:immunology / Q000502:physiology; D004195:Disease Models, Animal; D006967:Hypersensitivity / Q000276:immunology / Q000473:pathology; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D016023:Integrins / Q000037:antagonists & inhibitors*; D008968:Molecular Conformation; D015394:Molecular Structure; D010649:Phenylalanine / Q000737:chemistry; D012756:Sheep; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000596:Amino Acids; D000911:Antibodies, Monoclonal; D000947:Antigens, Helminth; D001372:Aza Compounds; D039041:Integrin alpha4beta1; D016023:Integrins; D013449:Sulfonamides; C071777:integrin alpha4beta7; D010649:Phenylalanine