RESUMO
In this study, we aimed to synthesize a novel blocker of transient receptor potential canonical 6 (TRPC6). The sp2 carbon atoms of the aminoindane skeleton of the known inhibitor were replaced with sp3 carbon atoms to increase the molecular complexity, measured by fraction sp3 (Fsp3). The representative compound, a bicyclo[4.3.0]nonane derivative DS88790512, inhibited TRPC6 with an IC50 value of 11â¯nM. Notably, DS88790512 exhibited excellent selectivity against hERG and hNaV1.5 channels, and was identified as an orally bioavailable compound.
Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Descoberta de Drogas , Indanos/farmacologia , Canal de Cátion TRPC6/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Bloqueadores dos Canais de Cálcio/administração & dosagem , Bloqueadores dos Canais de Cálcio/química , Relação Dose-Resposta a Droga , Humanos , Indanos/administração & dosagem , Indanos/química , Camundongos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Relação Estrutura-Atividade , Canal de Cátion TRPC6/metabolismoRESUMO
The enantioselective total synthesis of (-)-tetrodotoxin [(-)-TTX] and 4,9-anhydrotetrodotoxin, which are selective blockers of voltage-gated sodium channels, was accomplished from the commercially available p-benzoquinone. This synthesis was based on efficient stereocontrol of the six contiguous stereogenic centers on the core cyclohexane ring through Ogasawara's method, [3,3]-sigmatropic rearrangement of an allylic cyanate, and intramolecular 1,3-dipolar cycloaddition of a nitrile oxide. Our synthetic route was applied to the synthesis of the tetrodotoxin congeners 11-norTTX-6(R)-ol and 4,9-anhydro-11-norTTX-6(R)-ol through late-stage modification of the common intermediate. Neutral deprotection at the final step enabled easy purification of tetrodotoxin and 11-norTTX-6(R)-ol without competing dehydration to their 4,9-anhydro forms.
