Challenges in the development of an M4 PAM preclinical candidate: The discovery, SAR, and in vivo characterization of a series of 3-aminoazetidine-derived amides.
Bioorg Med Chem Lett
; 27(13): 2990-2995, 2017 07 01.
Article
em En
| MEDLINE
| ID: mdl-28522253
ABSTRACT
This letter details the continued chemical optimization of a novel series of M4 positive allosteric modulators (PAMs) based on a 5-amino-thieno[2,3-c]pyridazine core by incorporating a 3-amino azetidine amide moiety. The analogs described within this work represent the most potent M4 PAMs reported for this series to date. The SAR to address potency, clearance, subtype selectivity, CNS exposure, and P-gp efflux are described. This work culminated in the discovery of VU6000918, which demonstrated robust efficacy in a rat amphetamine-induced hyperlocomotion reversal model at a minimum efficacious dose of 0.3mg/kg.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Azetidinas
/
Receptor Muscarínico M4
/
Amidas
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article