1-Arylpiperazinyl-4-cyclohexylamine derived isoindole-1,3-diones as potent and selective alpha-1a/1d adrenergic receptor ligands

Shengjian Li; George Chiu; Virginia L Pulito; Jingchun Liu; Peter J Connolly; Steven A Middleton

doi:10.1016/j.bmcl.2006.12.111

1-Arylpiperazinyl-4-cyclohexylamine derived isoindole-1,3-diones as potent and selective alpha-1a/1d adrenergic receptor ligands

Bioorg Med Chem Lett. 2007 Mar 15;17(6):1646-50. doi: 10.1016/j.bmcl.2006.12.111. Epub 2007 Jan 12.

Authors

Shengjian Li¹, George Chiu, Virginia L Pulito, Jingchun Liu, Peter J Connolly, Steven A Middleton

Affiliation

¹ Johnson & Johnson Pharmaceutical Research and Development LLC, Drug Discovery Research, PO Box 300, 1000 Route 202 South, Raritan, NJ 08869, USA. sli3@prdus.jnj.com

PMID: 17254786
DOI: 10.1016/j.bmcl.2006.12.111

Abstract

Subtype-selective alpha-1a and/or alpha-1d adrenergic receptor antagonists may be useful for the treatment of benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS) with fewer adverse effects than non-selective drugs. A series of 1-arylpiperazinyl-4-cyclohexylamine derived isoindole-1,3-diones has been synthesized, displaying in vitro alpha(1a) and alpha(1d) binding affinity K(i) values in the range of 0.09-38nM with K(i)(alpha1b)/K(i)(alpha1a) and K(i)(alpha1b)/K(i)(alpha1d) selectivity ratios up to 3607-fold.

MeSH terms

Adrenergic alpha-Antagonists / chemical synthesis*
Adrenergic alpha-Antagonists / pharmacology*
Indicators and Reagents
Indoles / chemical synthesis*
Indoles / pharmacology*
Kinetics
Ligands
Magnetic Resonance Spectroscopy
Piperazines / chemical synthesis*
Piperazines / pharmacology*
Radiopharmaceuticals
Receptors, Adrenergic, alpha-1 / drug effects*
Stereoisomerism
Structure-Activity Relationship
Tetralones

Substances

Adrenergic alpha-Antagonists
Indicators and Reagents
Indoles
Ligands
Piperazines
Radiopharmaceuticals
Receptors, Adrenergic, alpha-1
Tetralones
2-(beta-(3-iodo-4-hydroxyphenyl)ethylaminomethyl)tetralone