Aza-bicyclic amino acid sulfonamides as alpha(4)beta(1)/alpha(4)beta(7) integrin antagonists.
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.
Dyatkin
Alexey B
AB
Drug Discovery, Johnson & Johnson Pharmaceutical Research & Development, LLC, Spring House, PA 19477-0776, USA. adyatkin@prdus.jnj.com
Hoekstra
William J
WJ
Kinney
William A
WA
Kontoyianni
Maria
M
Santulli
Rosemary J
RJ
Kimball
Edward S
ES
Fisher
M Carolyn
MC
Carolyn Fisher
M
M
Prouty
Stephen M
SM
Abraham
William M
WM
de Garavilla
Lawrence
L
Andrade-Gordon
Patricia
P
Hlasta
Dennis J
DJ
He
Wei
W
Hornby
Pamela J
PJ
Damiano
Bruce P
BP
Maryanoff
Bruce E
BE
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*
D000596:Amino Acids; D000911:Antibodies, Monoclonal; D000947:Antigens, Helminth; D001372:Aza Compounds; D039041:Integrin alpha4beta1; D016023:Integrins; D013449:Sulfonamides; C071777:integrin alpha4beta7; D010649:Phenylalanine