Discovery and optimization of substituted piperidines as potent, selective, CNS-penetrant α4β2 nicotinic acetylcholine receptor potentiators

被引：29

作者：

Albrecht, Brian K. ^{[1
]}

Berry, Virginia ^{[3
]}

Boezio, Alessandro A. ^{[1
]}

Cao, Lei ^{[3
]}

Clarkin, Kristie ^{[4
]}

Guo, Wenhong ^{[2
]}

Harmange, Jean-Christophe ^{[1
]}

Hierl, Markus ^{[2
]}

Huang, Liyue ^{[3
]}

Janosky, Brett ^{[3
]}

Knop, Johannes ^{[5
]}

Malmberg, Annika ^{[2
]}

McDermott, Jeff S. ^{[2
]}

Nguyen, Hung Q. ^{[4
]}

Springer, Stephanie K. ^{[1
]}

Waldon, Daniel ^{[3
]}

Woodin, Katrina ^{[1
]}

McDonough, Stefan I. ^{[2
]}

机构：

[1] Amgen Inc, Dept Med Chem, Cambridge, MA USA

[2] Amgen Inc, Dept Neurosci, Cambridge, MA USA

[3] Dept Pharmacokinet & Drug Metab, Cambridge, MA USA

[4] Dept Prot Sci, Thousand Oaks, CA 91320 USA

[5] Amgen Res GmbH, HTS Mol Pharmacol, D-93053 Regensburg, Germany

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 19期

关键词：

nicotinic receptor; positive modulation;

D O I：

10.1016/j.bmcl.2008.08.080

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The discovery of a series of small molecule alpha 4 beta 2 nAChR potentiators is reported. The structure-activity relationship leads to potent compounds selective against nAChRs including alpha 3 beta 2 and alpha 3 beta 4 and optimized for CNS penetrance. Compounds increased currents through recombinant alpha 4 beta 2 nAChRs, yet did not compete for binding with the orthosteric ligand cytisine. High potency and efficacy on the rat channel combined with good PK properties will allow testing of the a4b2 potentiator mechanism in animal models of disease. (C) 2008 Elsevier Ltd. All rights reserved.

引用

页码：5209 / 5212

页数：4

共 29 条

[1]

[Anonymous], [No title captured], Patent No. 2006021881

[2]

[Anonymous], 2000, HANDB EXP PHARM

[3] Recent Progress in the Development of Subtype Selective Nicotinic Acetylcholine Receptor Ligands [J].