The identification of 7-[(R)-2-((1S,2S)-2-benzyloxycyclopentylamino)-1- hydroxyethyl]-4-hydroxybenzothiazolone as an inhaled long-acting ß2-adrenoceptor agonist

The optimisation of two series of 4-hydroxybenzothiazolone derived ß2-adrenoceptor agonists, bearing a-substituted cyclopentyl and ß-phenethyl amino-substituents, as inhaled long-acting bronchodilators is described. Analogues were selected for synthesis using a lipophilicity based hypothesis to achieve the targeted rapid onset of action in combination with a long duration of action. The profiling of the two series led to identification of the a-substituted cyclopentyl analogue 2 as the optimal compound with a comparable profile to the inhaled once-daily long-acting ß2-adrenoceptor agonist indacaterol. On the basis of these data 2 was promoted as the backup development candidate to indacaterol from the Novartis LABA project. © 2014 Elsevier Ltd. All rights reserved

Discovery of Fevipiprant (NVP-QAW039), a Potent and Selective DP₂ Receptor Antagonist for Treatment of Asthma

Further optimization of an initial DP₂ receptor antagonist clinical candidate NVP-QAV680 led to the discovery of a follow-up molecule 2-(2-methyl-1-(4-(methylsulfonyl)-2-(trifluoromethyl)­benzyl)-1<i>H</i>-pyrrolo­[2,3-<i>b</i>]­pyridin-3-yl)­acetic acid (compound <b>11</b>, NVP-QAW039, fevipiprant), which exhibits improved potency on human eosinophils and Th2 cells, together with a longer receptor residence time, and is currently in clinical trials for severe asthma