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

The optimization of a cyclopentane-based hNK1 antagonist scaffold will be discussed in the context of enhanced water-solubility, sub-nanomolar hNK1 binding affinity, and oral activity in two in vivo models. The synthesis and optimization of a cyclopentane-based hNK1 antagonist scaffold 3, having fou...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2006-09, Vol.16 (17), p.4504-4511
Main 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.
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Biological and medical sciences
CHO Cells
Cricetinae
Cyclopentanes - adverse effects
Cyclopentanes - chemical synthesis
Cyclopentanes - chemistry
Cyclopentanes - pharmacology
Humans
Medical sciences
Molecular Structure
Neurokinin-1 Receptor Antagonists
Neurokinin-1: substance P
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
NK1 antagonist: cyclopentane-based structure
Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems
Pharmacology. Drug treatments
Receptors, Neurokinin-1 - genetics
Receptors, Neurokinin-1 - metabolism
Solubility
Structure-Activity Relationship
Water
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Summary:The optimization of a cyclopentane-based hNK1 antagonist scaffold will be discussed in the context of enhanced water-solubility, sub-nanomolar hNK1 binding affinity, and oral activity in two in vivo models. 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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2006.06.044