Design and optimization of cyclized NK1 antagonists with controlled atropisomeric properties

Abstract We have previously described a series of antagonists that showed high potency and selectivity for the NK 1 receptor. However, these compounds also had the undesirable property of existing as a mixture of four interconverting rotational isomers. Through biological and structural analysis of the atropisomers, a binding model was developed and used to guide the design of compounds, which were rigidified by installation of a cyclizing linkage. These compounds existed as a mixture of two atropisomers. Further elaboration of the ring system reinforced the desired conformation and eliminated atropisomeric properties. We found that the region distal to the 8-membered ring system could be modified while retaining NK 1 potency, and optimization led to further improvements in the in vivo activity.