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

Laura C Meurer; 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

doi:10.1016/j.bmcl.2006.06.044

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. Epub 2006 Jul 10.

Authors

Laura C Meurer¹, 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

Affiliation

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.

MeSH terms

Administration, Oral
Animals
CHO Cells
Cricetinae
Cyclopentanes / adverse effects
Cyclopentanes / chemical synthesis
Cyclopentanes / chemistry*
Cyclopentanes / pharmacology*
Humans
Molecular Structure
Neurokinin-1 Receptor Antagonists*
Receptors, Neurokinin-1 / genetics
Receptors, Neurokinin-1 / metabolism
Solubility
Structure-Activity Relationship
Water*

Substances

Cyclopentanes
Neurokinin-1 Receptor Antagonists
Receptors, Neurokinin-1
Water