Discovery of novel steroidal histamine H3 receptor antagonists/inverse agonists. Part 2. Versatile steroidal carboxamide derivatives.
Bioorg Med Chem Lett
; 29(20): 126643, 2019 10 15.
Article
en En
| MEDLINE
| ID: mdl-31492518
ABSTRACT
To further proceed with our previous work, novel steroid-based histamine H3 receptor antagonists were identified and characterized. Using an 'amine-to-amide' modification strategy at position 17, in vitro and in vivo potent monoamino steroid derivatives were found during the lead optimization. Usage of the non-basic amide moiety resulted in beneficial effects both in activity and selectivity. The 15α-carboxamido derivative 10 was not only highly active at human and rat H3 receptors, but also showed negligible activity at rat muscarinic receptors. Furthermore, it proved to be considerably stable in human and rat microsomes and showed significant in vivo potency in the pharmacodynamic rat dipsogenia test and in the water-labyrinth cognitive model. Based on all of these considerations, compound 10 was appointed to be a preclinical candidate.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Receptores Histamínicos H3
/
Amidas
/
Antagonistas de los Receptores Histamínicos
Límite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
Bioorg Med Chem Lett
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2019
Tipo del documento:
Article