RESUMO
Benzothiazole amides were identified as TRPV1 antagonists from high throughput screening using recombinant human TRPV1 receptor and structure-activity relationships were explored to pinpoint key pharmacophore interactions. By increasing aqueous solubility, through the attachment of polar groups to the benzothiazole core, and enhancing metabolic stability, by blocking metabolic sites, the drug-like properties and pharmokinetic profiles of benzothiazole compounds were sufficiently optimized such that their therapeutic potential could be verified in rat pharmacological models of pain.
Assuntos
Amidas/farmacologia , Benzotiazóis/farmacologia , Dor/tratamento farmacológico , Canais de Cátion TRPV/antagonistas & inibidores , Amidas/administração & dosagem , Amidas/química , Animais , Benzotiazóis/administração & dosagem , Benzotiazóis/química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Inflamação/tratamento farmacológico , Estrutura Molecular , Ratos , Proteínas Recombinantes/antagonistas & inibidores , Solubilidade , Relação Estrutura-AtividadeRESUMO
(+)- or (-)-p-Menthane-3-carboxaldehyde is made in two easy steps from (+)- or (-)-menthone, respectively. This auxiliary allows for the synthesis of carbonyl compounds bearing a alpha-chiral quaternary carbon. The flexibility, efficiency, and ease of use of the method are demonstrated in a series of examples, which include the total synthesis of (+)-cuparenone as well as a partial synthesis of (-)-cassiol.
