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Design and optimization of selective azaindole amide M 1 positive allosteric modulators

2015; Elsevier BV; Volume: 26; Issue: 2 Linguagem: Inglês

10.1016/j.bmcl.2015.11.053

1464-3405

Jennifer E. Davoren, Steven V. O’Neil, Dennis P. Anderson, Michael A. Brodney, Lois K. Chenard, Keith Dlugolenski, Jeremy R. Edgerton, Michael Green, Michelle R. Garnsey, Sarah Grimwood, Anthony R. Harris, Gregory W. Kauffman, Erik LaChapelle, John T. Lazzaro, Che‐Wah Lee, Susan M. Lotarski, Deane M. Nason, R. Scott Obach, Veronica Reinhart, Romelia Salomón–Ferrer, Stefanus J. Steyn, Damien Webb, Jiangli Yan, Lei Zhang,

Neuroscience and Neuropharmacology Research

Selective activation of the M1 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 M1 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.