RESUMO
The synthesis and SAR of a new series of LXR agonist is reported. The N-Aryl-3,3,3-trifluoro-2-hydroxy-2-methyl-propionamide hits were found in a limited screen of the AstraZeneca compound collection. The effort to optimize these hits into LXRbeta selectivity is described. Compound 20 displayed desirable pharmacokinetic profile and up regulation of ABCA1 and ABCG1 mRNA in the brain were achieved when evaluated in vivo in mice.
Assuntos
Amidas/farmacologia , Proteínas de Ligação a DNA/agonistas , Lactatos/farmacologia , Receptores Citoplasmáticos e Nucleares/agonistas , Sulfonamidas/farmacologia , Transportador 1 de Cassete de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/metabolismo , Amidas/síntese química , Amidas/química , Animais , Encéfalo/metabolismo , Linhagem Celular , Simulação por Computador , Proteínas de Ligação a DNA/metabolismo , Genes Reporter , Humanos , Lactatos/síntese química , Lactatos/química , Receptores X do Fígado , Camundongos , Receptores Nucleares Órfãos , Receptores Citoplasmáticos e Nucleares/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Regulação para CimaRESUMO
AZD3043 (previously named THRX-918661) is a novel short-acting intravenous anesthetic agent in clinical trials. Although AZD3043 is a positive modulator at the γ-aminobutyric acid (GABA)(A)-receptor, its potency and efficacy have not been characterized in detail. Nor is it known whether the point-mutations in the ß-subunit of the GABA(A)-receptor that dramatically reduce the anesthetic effect of propofol (i.e. ß2 (N289M) and ß3 (N290M)), also influence the effect of AZD3043. This study investigated the in vitro pharmacology of AZD3043 at the most common human GABA(A) receptor subtypes. Subunits of four human wild-type (α1ß2, α1ß2γ2, α2ß2γ2 and α2ß3γ2) and two mutant (α1ß2(N289M)γ2 and α2ß3(N290M)γ2) GABA(A) receptor channels were introduced into Xenopus oocytes and studied with two-electrode voltage-clamp. AZD3043 potentiated and directly activated the α1ß2γ2, α2ß2γ2 and α2ß3γ2 GABA(A) receptor subtypes. Moreover, both potency and efficacy of AZD3043 were reduced at the mutant α1ß2(N289M)γ2 and α2ß3(N290M)γ2 subtypes. AZD3043 increased the GABA response also in GABA(A) receptors lacking the γ2-subunit, i.e. α1ß2. In conclusion, AZD3043 is a positive modulator and a direct agonist at human GABA(A) receptors and is not dependent on the γ2-subunit for its effect. Similar to propofol, the effect of AZD3043 is dramatically reduced by point-mutations in the ß2(N289M) and ß3(N290M) subunits, indicating similar molecular mechanisms of action for propofol and AZD3043 at the human GABA(A) receptor.