A multivalent approach to the discovery of long-acting beta 2-adrenoceptor agonists for the treatment of asthma and COPD

• Published in: Bioorganic & medicinal chemistry letters Vol. 22; no. 2; pp. 1213 - 1218
• Main Authors: Jacobsen, John R, Choi, Seok Ki, Combs, Jesse, Fournier, Eric JL, Klein, Uwe, Pfeiffer, Juergen W, Thomas, GRoger, Yu, Cecile, Moran, Edmund J
• Format: Journal Article
• Language: English
• Published: 15-01-2012
• ISSN: 0960-894X
• DOI: 10.1016/j.bmcl.2011.11.072

A multivalent approach was applied to the design of long-acting inhaled beta 2-adrenoceptor agonists. A series of dimeric arylethanolamines based on the short acting beta 2-adrenoceptor agonist albuterol were prepared, varying the nature and length of the linker between the basic nitrogens. None of the C2-symmetric dimers demonstrated increased potency, however dimer 5j, derived from 4-phenethylamine, was found to have increased binding potency in vitro relative to the parent monomer. Optimization of this structure led to the identification of 22 (milveterol) which demonstrates high potency in vitro and long duration of action in a guinea pig model of bronchoprotection.