Selection of a 2-azabicyclo[2.2.2]octane-based alpha4beta1 integrin antagonist as an inhaled anti-asthmatic agent.
The alpha4beta1 integrin, expressed on eosinophils and neutrophils, induces inflammation in the lung by facilitating cellular infiltration and activation. From a number of potent alpha4beta1 antagonists that we evaluated for safety and efficacy, 1 was selected as a lead candidate for anti-asthma therapy by the inhalation route. We devised an optimized stereoselective synthesis to facilitate the preparation of a sufficiently large quantity of 1 for assessment in vivo. Administration of 1 to allergen-sensitive sheep by inhalation blocked the late-phase response of asthma and abolished airway hyper-responsiveness at 24h following the antigen challenge. Additionally, the recruitment of inflammatory cells into the lungs was inhibited. Administration of 1 to ovalbumin-sensitized guinea pigs intraperitoneally blocked airway resistance and inhibited the recruitment of inflammatory cells.
Research & Early Development, Johnson & Johnson Pharmaceutical Research & Development, Welsh and McKean Roads, Spring House, PA 19477-0776, USA. elawson@prdus.jnj.com
Edward C
EC
Lawson
Rosemary J
RJ
Santulli
Alexey B
AB
Dyatkin
Scott A
SA
Ballentine
William M
WM
Abraham
Sandra
S
Rudman
Clive P
CP
Page
Lawrence
L
de Garavilla
Bruce P
BP
Damiano
William A
WA
Kinney
Bruce E
BE
Maryanoff
D000280:Administration, Inhalation; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry*; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D004334:Drug Administration Schedule; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007274:Injections, Intraperitoneal; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D008297:Male; D008968:Molecular Conformation; D010047:Ovalbumin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D012129:Respiratory Function Tests; D012137:Respiratory System / Q000187:drug effects / Q000503:physiopathology; D012756:Sheep; D013329:Structure-Activity Relationship
D018927:Anti-Asthmatic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D039041:Integrin alpha4beta1; D010047:Ovalbumin