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

  • Bioorg Med Chem Lett. 2006 Sep 1;16(17):4497-503. doi: 10.1016/j.bmcl.2006.06.035.
Paul E Finke  1 ,  Laura C Meurer ,  Dorothy A Levorse ,  Sander G Mills ,  Malcolm Maccoss ,  Sharon Sadowski ,  Margaret A Cascieri ,  Kwei-Lan Tsao ,  Gary G Chicchi ,  Joseph M Metzger ,  D Euan Macintyre
Affiliations
  • 1. Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. [email protected]
PMID: 16824752 DOI: 10.1016/j.bmcl.2006.06.035
Abstract

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.