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

  • Bioorg Med Chem Lett. 2006 Sep 1;16(17):4504-11. doi: 10.1016/j.bmcl.2006.06.044.
Laura C Meurer  1 ,  Paul E Finke ,  Karen A Owens ,  Nancy N Tsou ,  Richard G Ball ,  Sander G Mills ,  Malcolm Maccoss ,  Sharon Sadowski ,  Margaret A Cascieri ,  Kwei-Lan Tsao ,  Gary G Chicchi ,  Linda A Egger ,  Silvi Luell ,  Joseph M Metzger ,  D Euan Macintyre ,  Nadia M J Rupniak ,  Angela R Williams ,  Richard J Hargreaves
Affiliations
  • 1. Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. [email protected]
PMID: 16831551 DOI: 10.1016/j.bmcl.2006.06.044
Abstract

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.