Multiparameter exploration of piperazine derivatives as δ-opioid receptor agonists for CNS indications

A novel series of piperazine derivatives exhibits sub-nanomolar binding and enhanced subtype selectivity as δ-opioid agonists. The synthesis and SAR are described as well as the application of computational models to improve in vitro ADME and safety properties suitable for CNS indications, specifica...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2012-01, Vol.22 (2), p.1169-1173
Hauptverfasser:	McCauley, John P., Dantzman, Cathy L., King, Megan M., Ernst, Glen E., Wang, Xia, Brush, Kelly, Palmer, William E., Frietze, William, Andisik, Donald W., Hoesch, Valerie, Doring, Kenneth, Hulsizer, James, Bui, Khanh H., Liu, Jay, Hudzik, Thomas J., Wesolowski, Steven S.
Format:	Artikel
Sprache:	eng
Schlagworte:	ADME predictive models agonists Animals Biological and medical sciences Central nervous system Central Nervous System - drug effects Central Nervous System - metabolism chemistry Computer Simulation Delta opioid agonist Dogs Dose-Response Relationship, Drug Ether-A-Go-Go Potassium Channels - antagonists & inhibitors hERG HERG protein Humans Mathematical models Medical sciences Microsomal clearance Molecular Structure Opioid receptors (type delta) Permeability Pharmacology. Drug treatments piperazine Piperazines - chemical synthesis Piperazines - chemistry Piperazines - pharmacology Potassium channels (voltage-gated) Receptors, Opioid, delta - agonists Receptors, Opioid, delta - metabolism Stereoisomerism Structure-Activity Relationship
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Zusammenfassung:	A novel series of piperazine derivatives exhibits sub-nanomolar binding and enhanced subtype selectivity as δ-opioid agonists. The synthesis and SAR are described as well as the application of computational models to improve in vitro ADME and safety properties suitable for CNS indications, specifically microsomal clearance, permeability, and hERG channel inhibition. A novel series of piperazine derivatives exhibits sub-nanomolar binding and enhanced subtype selectivity as δ-opioid agonists. The synthesis and SAR are described as well as the application of computational models to improve in vitro ADME and safety properties suitable for CNS indications, specifically microsomal clearance, permeability, and hERG channel inhibition.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2011.11.088