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The Discovery of Vilanterol Based on Structure-Activity Relationships (SAR) and the Antedrug Approach

Procopiou PA.

RDD Europe 2011. Volume 1, 2011: 11-20.

Abstract:

In the last decade there has been great interest in the discovery of a once-daily β2-adrenoceptor agonist to be used as a part of a combination of drugs for the topical treatment of asthma and chronic obstructive pulmonary disease (COPD). The objective of this program of work was to identify candidates showing reduced systemic exposure/improved therapeutic index, and/or an inherently longer duration of action at the β2-adrenoceptor. After investigating a number of possible approaches we adopted an antedrug to improve the therapeutic index. Antedrugs in this case are delivered topically by inhalation, but they undergo rapid metabolism into non-toxic, inactive metabolites following entry into the systemic circulation. Because salmeterol is known to be metabolized in humans by benzylic hydroxylation to α-hydroxy salmeterol, we investigated whether the replacement of a single methylene of the salmeterol chain with an oxygen atom could enable reduced plasma lifetimes. The selection of vilanterol (GW642444) from a series of analogues is described below. The triphenylacetate salt of this new long acting β2-agonist demonstrates 24 h duration of action in asthma and COPD patients, and is currently undergoing Phase III clinical trials for both asthma and COPD.