Design and optimization of selective azaindole amide M1 positive allosteric modulators.
Bioorg Med Chem Lett
; 26(2): 650-655, 2016 Jan 15.
Article
in En
| MEDLINE
| ID: mdl-26631313
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.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
Receptor, Muscarinic M1
/
Allosteric Regulation
/
Amides
/
Indoles
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Bioorg Med Chem Lett
Journal subject:
BIOQUIMICA
/
QUIMICA
Year:
2016
Type:
Article