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Cyclopentane-based human NK1 antagonists. Part 2: development of potent, orally active, water-soluble derivatives |
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| Authors: | Meurer Laura C Finke Paul E Owens Karen A Tsou Nancy N Ball Richard G Mills Sander G Maccoss Malcolm Sadowski Sharon Cascieri Margaret A Tsao Kwei-Lan Chicchi Gary G Egger Linda A Luell Silvi Metzger Joseph M Macintyre D Euan Rupniak Nadia M J Williams Angela R Hargreaves Richard J |
| Affiliation: | Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. laura_meurer@merck.com |
| 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. |
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