Cyclopentane-based human NK1 antagonists. Part 2: Development of potent, orally active, water-soluble derivatives

The optimization of a cyclopentane-based hNK1 antagonist scaffold will be discussed in the context of enhanced water-solubility, sub-nanomolar hNK1 binding affinity, and oral activity in two in vivo models. The synthesis and optimization of a cyclopentane-based hNK1 antagonist scaffold 3, having four chiral centers, will be discussed in the context of its enhanced water solubility properties relative to the marketed anti-emetic hNK1 antagonist EMEND ® (Aprepitant). Sub-nanomolar hNK1 binding was achieved and oral activity comparable to Aprepitant in two in vivo models will be described.