Design and optimization of selective azaindole amide M1 positive allosteric modulators

  • Bioorg Med Chem Lett. 2016 Jan 15;26(2):650-655. doi: 10.1016/j.bmcl.2015.11.053.
Jennifer E Davoren  1 ,  Steven V O'Neil  2 ,  Dennis P Anderson  2 ,  Michael A Brodney  3 ,  Lois Chenard  2 ,  Keith Dlugolenski  4 ,  Jeremy R Edgerton  4 ,  Michael Green  3 ,  Michelle Garnsey  2 ,  Sarah Grimwood  4 ,  Anthony R Harris  2 ,  Gregory W Kauffman  2 ,  Erik LaChapelle  2 ,  John T Lazzaro  5 ,  Che-Wah Lee  2 ,  Susan M Lotarski  4 ,  Deane M Nason  2 ,  R Scott Obach  6 ,  Veronica Reinhart  4 ,  Romelia Salomon-Ferrer  3 ,  Stefanus J Steyn  7 ,  Damien Webb  3 ,  Jiangli Yan  2 ,  Lei Zhang  3
Affiliations
  • 1. Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Cambridge, MA 02139, United States. Electronic address: [email protected].
  • 2. Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Groton, CT 06340, United States.
  • 3. Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Cambridge, MA 02139, United States.
  • 4. Neuroscience and Pain Research Unit, Pfizer Worldwide Research and Development, Cambridge, MA 02139, United States.
  • 5. Primary Pharmacology Group, Pfizer Worldwide Research and Development, Groton, CT 06340, United States.
  • 6. Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research and Development, Groton, CT 06340, United States.
  • 7. Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research and Development, Cambridge, MA 02139, United States.
PMID: 26631313 DOI: 10.1016/j.bmcl.2015.11.053
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.

Keywords
Azaindole amide; Intra-molecular hydrogen bond (IMHB); M(1) positive allosteric modulator (PAM); M(1) selective activator.
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