367261-25-4Relevant academic research and scientific papers
Design and optimization of cyclized NK1 antagonists with controlled atropisomeric properties
Albert, Jeffrey S.,Ohnmacht, Cyrus,Bernstein, Peter R.,Rumsey, William L.,Aharony, David,Masek, Brian B.,Dembofsky, Bruce T.,Koether, Gerard M.,Potts, William,Evenden, John L.
, p. 4337 - 4347 (2004)
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.
