Author/Authors :
Jeffrey S Albert، نويسنده , , Cyrus Ohnmacht، نويسنده , , Peter R Bernstein، نويسنده , , William L. Rumsey، نويسنده , , David Aharony، نويسنده , , Brian B Masek، نويسنده , , Bruce T. Dembofsky، نويسنده , , Gerard M Koether، نويسنده , , William Potts، نويسنده , , John L Evenden، نويسنده ,
Abstract :
We have previously described a series of antagonists that showed high potency and selectivity for the NK1 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 NK1 potency, and optimization led to further improvements in the in vivo activity.
