Optimisation of imidazole compounds as selective TAAR1 agonists: discovery of RO5073012.
Bioorg Med Chem Lett
; 22(16): 5244-8, 2012 Aug 15.
Article
em En
| MEDLINE
| ID: mdl-22795332
ABSTRACT
A series of imidazole compounds has been identified which affords potent and selective partial and full agonists of the TAAR1 receptor. Starting from 2-benzyl-imidazoline screening hits, a series of structurally related 2-benzyl- and 4-benzyl-imidazoles was investigated first, but it proved highly challenging to obtain compounds having sufficient selectivity against the adrenergic alpha 2 receptor. This issue could be successfully addressed by modification of the linker region and SAR exploration led to the discovery of highly selective isopropyl-substituted 4-aminomethyl-imidazole compounds. The work culminated in the identification of the selective TAAR1 partial agonist RO5073012 (4-chlorophenyl)-(1H-imidazol-4-ylmethyl)-isopropyl-amine, 24), which has a good pharmacokinetic profile after oral administration in rodents. RO5073012 has been found to be active in a behavioural rat model which is considered indicative for schizophrenia.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Receptores Acoplados a Proteínas G
/
Imidazóis
/
Compostos de Anilina
Limite:
Animals
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article