Synthesis and SAR investigations for novel melanin-concentrating hormone 1 receptor (MCH1) antagonists part 2: A hybrid strategy combining key fragments of HTS hits.
J Med Chem
; 50(16): 3883-90, 2007 Aug 09.
Article
em En
| MEDLINE
| ID: mdl-17668922
ABSTRACT
A novel series of melanin-concentrating hormone (MCH1) receptor antagonists based on combining key fragments from the high-throughput screening (HTS) hits compound 2 (SNAP 7941) and compound 5 (chlorohaloperidol) are described. The resultant analogs, exemplified by compounds 11a-11h, 15a-15h, and 16a-16g, were evaluated in in vitro and in vivo assays for their potential in treatment of mood disorders. From further SAR investigations, N-(3-{1-[4-(3,4-difluorophenoxy)benzyl]-4-piperidinyl}-4-methylphenyl)-2-methylpropanamide (16g, SNAP 94847) was identified to be a high affinity and selective ligand for the MCH1 receptor. Compound 16g also shows good oral bioavailability (59%) and exhibits a brain/plasma ratio of 2.3 in rats. Compound 16g showed in vivo inhibition of a centrally induced MCH-induced drinking effect and exhibited a dose-dependent anxiolytic effect in the rat social interaction model.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Piperidinas
/
Ansiolíticos
/
Proteínas do Citoesqueleto
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Haloperidol
Limite:
Animals
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Humans
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Male
Idioma:
En
Ano de publicação:
2007
Tipo de documento:
Article