Bicyclic Heterocyclic Replacement of an Aryl Amide Leading to Potent and Kinase-Selective Adaptor Protein 2-Associated Kinase 1 Inhibitors.
J Med Chem
; 65(5): 4121-4155, 2022 03 10.
Article
en En
| MEDLINE
| ID: mdl-35171586
ABSTRACT
Adaptor protein 2-associated kinase 1 (AAK1) is a serine/threonine kinase that was identified as a therapeutic target for the potential treatment of neuropathic pain. Inhibition of AAK1 in the central nervous system, particularly within the spinal cord, was found to be the relevant site for achieving an antinociceptive effect. We previously reported that compound 7 is a brain-penetrant, AAK1 inhibitor that showed efficacy in animal models for neuropathic pain. One approach we took to improve upon the potency of 7 involved tying the amide back into the neighboring phenyl ring to form a bicyclic heterocycle. Investigation of the structure-activity relationships (SARs) of substituents on the resultant quinazoline and quinoline ring systems led to the identification of (S)-31, a brain-penetrant, AAK1-selective inhibitor with improved enzyme and cellular potency compared to 7. The synthesis, SAR, and in vivo evaluation of a series of quinazoline and quinoline-based AAK1 inhibitors are described herein.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Quinolinas
/
Neuralgia
Tipo de estudio:
Risk_factors_studies
Límite:
Animals
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2022
Tipo del documento:
Article
País de afiliación:
Estados Unidos