4-Piperidin-4-ylidenemethyl-benzamides as δ-opioid receptor agonists for CNS indications: identifying clinical candidates

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

doi:10.1016/j.bmcl.2011.11.089

4-Piperidin-4-ylidenemethyl-benzamides as δ-opioid receptor agonists for CNS indications: identifying clinical candidates

Bioorg Med Chem Lett. 2012 Jan 15;22(2):1174-8. doi: 10.1016/j.bmcl.2011.11.089. Epub 2011 Nov 30.

Authors

Cathy L Dantzman¹, Megan M King, Glen E Ernst, Xia Wang, John P McCauley Jr, Donald W Andisik, Kelly Brush, Khanh H Bui, William Frietze, Valerie Hoesch, Jay Liu, William E Palmer, Nathan Spear, Thomas J Hudzik, Steven S Wesolowski

Affiliation

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

PMID: 22197137
DOI: 10.1016/j.bmcl.2011.11.089

Abstract

A series of 4-piperidin-4-ylidenemethyl-benzamide δ-opioid receptor agonists is described with an emphasis on balancing the potency, subtype selectivity and in vitro ADME and safety properties. The three sites impacting SAR are substitutions on the aryl group (R(1)), the piperidine nitrogen (R(2)), and the amide (R(3)). Each region contributes to the balance of properties for δ opioid activity and a desirable CNS profile, and two clinical candidates (20 and 24) were advanced.

MeSH terms

Benzamides / chemistry
Benzamides / pharmacology*
Central Nervous System / drug effects*
Central Nervous System / metabolism
Dose-Response Relationship, Drug
Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
HEK293 Cells
Humans
Molecular Structure
Piperidines / chemistry
Piperidines / pharmacology*
Receptors, Opioid, delta / agonists*
Receptors, Opioid, delta / metabolism
Stereoisomerism
Structure-Activity Relationship

Substances

Benzamides
Ether-A-Go-Go Potassium Channels
Piperidines
Receptors, Opioid, delta