Discovery of (3-endo)-3-(2-cyano-2,2-diphenylethyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octane bromide as an efficacious inhaled muscarinic acetylcholine receptor antagonist for the treatment of COPD

Zehong Wan; Dramane I Laine; Hongxing Yan; Chongjie Zhu; Katherine L Widdowson; Peter T Buckley; Miriam Burman; James J Foley; Henry M Sarau; Dulcie B Schmidt; Edward F Webb; Kristen E Belmonte; Michael Palovich

doi:10.1016/j.bmcl.2009.07.006

Discovery of (3-endo)-3-(2-cyano-2,2-diphenylethyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octane bromide as an efficacious inhaled muscarinic acetylcholine receptor antagonist for the treatment of COPD

Bioorg Med Chem Lett. 2009 Aug 15;19(16):4560-2. doi: 10.1016/j.bmcl.2009.07.006. Epub 2009 Jul 8.

Authors

Zehong Wan¹, Dramane I Laine, Hongxing Yan, Chongjie Zhu, Katherine L Widdowson, Peter T Buckley, Miriam Burman, James J Foley, Henry M Sarau, Dulcie B Schmidt, Edward F Webb, Kristen E Belmonte, Michael Palovich

Affiliation

¹ Respiratory Centre of Excellence for Drug Discovery, Research and Development, GlaxoSmithKline Pharmaceuticals, King of Prussia, PA 19406, USA. [email protected]

PMID: 19616944
DOI: 10.1016/j.bmcl.2009.07.006

Abstract

Design and syntheses of a novel series of muscarinic antagonists are reported. These efforts have culminated in the discovery of (3-endo)-3-(2-cyano-2,2-diphenylethyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octane bromide (4a) as a potent and pan-active muscarinic antagonist as well as a functionally active compound in a murine model of bronchoconstriction. The compound has also displayed pharmacokinetic characteristics suitable for inhaled delivery.

MeSH terms

Administration, Inhalation
Animals
Biphenyl Compounds / chemical synthesis
Biphenyl Compounds / chemistry*
Biphenyl Compounds / pharmacokinetics
Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis
Bridged Bicyclo Compounds, Heterocyclic / chemistry*
Bridged Bicyclo Compounds, Heterocyclic / pharmacokinetics
Drug Discovery
Humans
Mice
Muscarinic Antagonists / chemical synthesis
Muscarinic Antagonists / chemistry*
Muscarinic Antagonists / pharmacokinetics
Pulmonary Disease, Chronic Obstructive / drug therapy*
Rats
Receptors, Muscarinic / chemistry*
Receptors, Muscarinic / metabolism
Structure-Activity Relationship

Substances

(3-endo)-3-(2-cyano-2,2-diphenylethyl)-8,8-dimethyl-8-azoniabicyclo( 3.2.1)octane bromide
Biphenyl Compounds
Bridged Bicyclo Compounds, Heterocyclic
Muscarinic Antagonists
Receptors, Muscarinic