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

John P McCauley Jr; Cathy L Dantzman; Megan M King; Glen E Ernst; Xia Wang; Kelly Brush; William E Palmer; William Frietze; Donald W Andisik; Valerie Hoesch; Kenneth Doring; James Hulsizer; Khanh H Bui; Jay Liu; Thomas J Hudzik; Steven S Wesolowski

doi:10.1016/j.bmcl.2011.11.088

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

Bioorg Med Chem Lett. 2012 Jan 15;22(2):1169-73. doi: 10.1016/j.bmcl.2011.11.088. Epub 2011 Dec 7.

Authors

John P McCauley Jr¹, Cathy L Dantzman, Megan M King, Glen E Ernst, Xia Wang, Kelly Brush, William E Palmer, William Frietze, Donald W Andisik, Valerie Hoesch, Kenneth Doring, James Hulsizer, Khanh H Bui, Jay Liu, Thomas J Hudzik, Steven S Wesolowski

Affiliation

¹ AstraZeneca Pharmaceuticals, 1800 Concord Pike, Wilmington, DE 19850, USA.

PMID: 22197139
DOI: 10.1016/j.bmcl.2011.11.088

Abstract

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.

MeSH terms

Animals
Central Nervous System / drug effects*
Central Nervous System / metabolism
Computer Simulation
Dogs
Dose-Response Relationship, Drug
Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
Humans
Molecular Structure
Piperazines / chemical synthesis
Piperazines / chemistry
Piperazines / pharmacology*
Receptors, Opioid, delta / agonists*
Receptors, Opioid, delta / metabolism
Stereoisomerism
Structure-Activity Relationship

Substances

Ether-A-Go-Go Potassium Channels
Piperazines
Receptors, Opioid, delta