Design and optimization of selective azaindole amide M1 positive allosteric modulators

被引：37

作者：

Davoren, Jennifer E. ^{[1
]}

O'Neil, Steven V. ^{[4
]}

Anderson, Dennis P. ^{[4
]}

Brodney, Michael A. ^{[1
]}

Chenard, Lois ^{[4
]}

Dlugolenski, Keith ^{[2
]}

Edgerton, Jeremy R. ^{[2
]}

Green, Michael ^{[1
]}

Garnsey, Michelle ^{[4
]}

Grimwood, Sarah ^{[2
]}

Harris, Anthony R. ^{[4
]}

Kauffman, Gregory W. ^{[4
]}

LaChapelle, Erik ^{[4
]}

Lazzaro, John T. ^{[6
]}

Lee, Che-Wah ^{[4
]}

Lotarski, Susan M. ^{[2
]}

Nason, Deane M. ^{[4
]}

Obach, R. Scott ^{[5
]}

Reinhart, Veronica ^{[2
]}

Salomon-Ferrer, Romelia ^{[1
]}

Steyn, Stefanus J. ^{[3
]}

Webba, Damien ^{[1
]}

Yan, Jiangli ^{[4
]}

Zhang, Lei ^{[1
]}

机构：

[1] Pfizer Worldwide Res & Dev, Worldwide Med Chem, Cambridge, MA 02139 USA

[2] Pfizer Worldwide Res & Dev, Neurosci & Pain Res Unit, Cambridge, MA 02139 USA

[3] Pfizer Worldwide Res & Dev, Pharmacokinet Dynam & Metab, Cambridge, MA 02139 USA

[4] Pfizer Worldwide Res & Dev, Worldwide Med Chem, Groton, CT 06340 USA

[5] Pfizer Worldwide Res & Dev, Pharmacokinet Dynam & Metab, Groton, CT 06340 USA

[6] Pfizer Worldwide Res & Dev, Primary Pharmacol Grp, Groton, CT 06340 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2016年 / 26卷 / 02期

关键词：

M-1 positive allosteric modulator (PAM); M-1 selective activator; Azaindole amide; Intra-molecular hydrogen bond (IMHB); MUSCARINIC RECEPTOR AGONIST; ALZHEIMERS-DISEASE; ACTIVATION; XANOMELINE; DISCOVERY; SERIES;

D O I：

10.1016/j.bmcl.2015.11.053

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Selective activation of the M-1 receptor via a positive allosteric modulator (PAM) is a new approach for the treatment of the cognitive impairments associated with schizophrenia and Alzheimer's disease. A novel series of azaindole amides and their key pharmacophore elements are described. The nitrogen of the azaindole core is a key design element as it forms an intramolecular hydrogen bond with the amide N-H thus reinforcing the bioactive conformation predicted by published SAR and our homology model. Representative compound 25 is a potent and selective M-1 PAM that has well aligned physicochemical properties, adequate brain penetration and pharmacokinetic (PK) properties, and is active in vivo. These favorable properties indicate that this series possesses suitable qualities for further development and studies. (C) 2015 Elsevier Ltd. All rights reserved.

引用

页码：650 / 655

页数：6

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