Discovery and structure-activity relationships of 2-benzylpyrrolidine-substituted aryloxypropanols as calcium-sensing receptor antagonists

Wu Yang; Yufeng Wang; Jacques Y Roberge; Zhengping Ma; Yalei Liu; R Michael Lawrence; David P Rotella; Ramakrishna Seethala; Jean H M Feyen; John K Dickson Jr

doi:10.1016/j.bmcl.2004.11.071

Discovery and structure-activity relationships of 2-benzylpyrrolidine-substituted aryloxypropanols as calcium-sensing receptor antagonists

Bioorg Med Chem Lett. 2005 Feb 15;15(4):1225-8. doi: 10.1016/j.bmcl.2004.11.071.

Authors

Wu Yang¹, Yufeng Wang, Jacques Y Roberge, Zhengping Ma, Yalei Liu, R Michael Lawrence, David P Rotella, Ramakrishna Seethala, Jean H M Feyen, John K Dickson Jr

Affiliation

¹ Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 5400, Princeton, NJ 08543-5400, USA. wu.yang@bms.com

PMID: 15686947
DOI: 10.1016/j.bmcl.2004.11.071

Abstract

A structure-activity relationship study of the amine portion of the calcilytic compound NPS-2143 resulted in the discovery of substituted 2-benzylpyrrolidines as replacements for the 1,1-dimethyl-2-naphthalen-2-yl-ethylamine. When compared to NPS-2143, a newly discovered compound, 3h, exhibited similar potency as a calcium-sensing receptor (CaR) antagonist and a superior human ether-a-go-go related gene (hERG) profile.

MeSH terms

Calcium Signaling / drug effects
ERG1 Potassium Channel
Ether-A-Go-Go Potassium Channels
Humans
Inhibitory Concentration 50
Naphthalenes / pharmacology
Patch-Clamp Techniques
Potassium Channels, Voltage-Gated / antagonists & inhibitors
Propanols / chemical synthesis*
Propanols / pharmacology
Receptors, Calcium-Sensing / antagonists & inhibitors*
Structure-Activity Relationship

Substances

ERG1 Potassium Channel
Ether-A-Go-Go Potassium Channels
KCNH2 protein, human
N-(2-hydroxy-3-(2-cyano-3-chlorophenoxy)propyl)-1,1-dimethyl-2-(2-nephthyl)ethylamine
Naphthalenes
Potassium Channels, Voltage-Gated
Propanols
Receptors, Calcium-Sensing