title: Design and optimization of selective azaindole amide M1 positive allosteric modulators.
abstract: 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.
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Cambridge, MA 02139, United States. Electronic address: jennifer.e.davoren@pfizer.com.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Davoren
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Groton, CT 06340, United States.
authors.forename: Steven V
authors.initials: SV
authors.lastname: O'Neil
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Groton, CT 06340, United States.
authors.forename: Dennis P
authors.initials: DP
authors.lastname: Anderson
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Cambridge, MA 02139, United States.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Brodney
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Groton, CT 06340, United States.
authors.forename: Lois
authors.initials: L
authors.lastname: Chenard
authors.affiliation: Neuroscience and Pain Research Unit, Pfizer Worldwide Research and Development, Cambridge, MA 02139, United States.
authors.forename: Keith
authors.initials: K
authors.lastname: Dlugolenski
authors.affiliation: Neuroscience and Pain Research Unit, Pfizer Worldwide Research and Development, Cambridge, MA 02139, United States.
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Edgerton
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Cambridge, MA 02139, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Green
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Groton, CT 06340, United States.
authors.forename: Michelle
authors.initials: M
authors.lastname: Garnsey
authors.affiliation: Neuroscience and Pain Research Unit, Pfizer Worldwide Research and Development, Cambridge, MA 02139, United States.
authors.forename: Sarah
authors.initials: S
authors.lastname: Grimwood
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Groton, CT 06340, United States.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Harris
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Groton, CT 06340, United States.
authors.forename: Gregory W
authors.initials: GW
authors.lastname: Kauffman
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Groton, CT 06340, United States.
authors.forename: Erik
authors.initials: E
authors.lastname: LaChapelle
authors.affiliation: Primary Pharmacology Group, Pfizer Worldwide Research and Development, Groton, CT 06340, United States.
authors.forename: John T
authors.initials: JT
authors.lastname: Lazzaro
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Groton, CT 06340, United States.
authors.forename: Che-Wah
authors.initials: CW
authors.lastname: Lee
authors.affiliation: Neuroscience and Pain Research Unit, Pfizer Worldwide Research and Development, Cambridge, MA 02139, United States.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Lotarski
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Groton, CT 06340, United States.
authors.forename: Deane M
authors.initials: DM
authors.lastname: Nason
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research and Development, Groton, CT 06340, United States.
authors.forename: R Scott
authors.initials: RS
authors.lastname: Obach
authors.affiliation: Neuroscience and Pain Research Unit, Pfizer Worldwide Research and Development, Cambridge, MA 02139, United States.
authors.forename: Veronica
authors.initials: V
authors.lastname: Reinhart
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Cambridge, MA 02139, United States.
authors.forename: Romelia
authors.initials: R
authors.lastname: Salomon-Ferrer
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research and Development, Cambridge, MA 02139, United States.
authors.forename: Stefanus J
authors.initials: SJ
authors.lastname: Steyn
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Cambridge, MA 02139, United States.
authors.forename: Damien
authors.initials: D
authors.lastname: Webb
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Groton, CT 06340, United States.
authors.forename: Jiangli
authors.initials: J
authors.lastname: Yan
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Cambridge, MA 02139, United States.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects*; D000577:Amides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D015195:Drug Design; D006801:Humans; D006860:Hydrogen Bonding; D007211:Indoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D062105:Molecular Docking Simulation; D043643:Receptor, Muscarinic M1 / Q000819:agonists / Q000378:metabolism*
chemical_list: C522780:4-azaindole; D000577:Amides; D007211:Indoles; D043643:Receptor, Muscarinic M1
keywords: Azaindole amide; Intra-molecular hydrogen bond (IMHB); M(1) positive allosteric modulator (PAM); M(1) selective activator