Cyclopentane-based human NK1 antagonists. Part 1: Discovery and initial SAR

An initial investigation of the novel cyclopentane scaffold 6 afforded low nanomolar human NK1 antagonists having enhanced water solubility properties compared to morpholine 1. A synthesis of this cyclopentane scaffold, having three contiguous chiral centers, and the unexpected determination that the 1,2-trans-2,3-trans-ring stereochemistry, as opposed to the cis-ether/phenyl configuration of the known structures 1–5, is optimal for this class of antagonist are described.

The synthesis and initial SAR of cyclopentane-based hNK1 antagonists is reported.Figure optionsDownload as PowerPoint slide