RESUMO
The Na(V)1.7 ion channel is an attractive target for development of potential analgesic drugs based on strong genetic links between mutations in the gene coding for the channel protein and inheritable pain conditions. The (S)-N-chroman-3-ylcarboxamide series, exemplified by 1, was used as a starting point for development of new channel blockers, resulting in the phenethyl nicotinamide series. The structure and activity relationship for this series was established and the metabolic issues of early analogues were addressed by appropriate substitutions. Compound 33 displayed acceptable overall in vitro properties and in vivo rat PK profile.
Assuntos
Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Bloqueadores dos Canais de Sódio/farmacologia , Animais , Relação Dose-Resposta a Droga , Humanos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Niacinamida/síntese química , Niacinamida/química , Ratos , Bloqueadores dos Canais de Sódio/síntese química , Bloqueadores dos Canais de Sódio/química , Solubilidade , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Recent findings showing a relation between mutations in the Na(V)1.7 channel in humans and altered pain sensation has contributed to increase the attractiveness of this ion channel as target for development of potential analgesics. Amido chromanes 1 and 2 were identified as blockers of the Na(V)1.7 channel and analogues with modifications of the 5-substituent and the carboxamide part of the molecule were prepared to establish the structure-activity relationship. Compounds 13 and 29 with good overall in vitro and in vivo rat PK profile were identified. Furthermore, 29 showed in vivo efficacy in a nociceptive pain model.
Assuntos
Cromanos/química , Cromanos/uso terapêutico , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Dor Nociceptiva/tratamento farmacológico , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Bloqueadores do Canal de Sódio Disparado por Voltagem/uso terapêutico , Analgésicos/química , Analgésicos/farmacocinética , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Cromanos/farmacocinética , Cromanos/farmacologia , Formaldeído , Humanos , Dor Nociceptiva/induzido quimicamente , Ratos , Relação Estrutura-Atividade , Bloqueadores do Canal de Sódio Disparado por Voltagem/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacocinéticaRESUMO
The voltage-gated sodium channel Na(V)1.7 is believed to be a critical mediator of pain sensation based on clinical genetic studies and pharmacological results. Clinical utility of nonselective sodium channel blockers is limited due to serious adverse drug effects. Here, we present the optimization, structure-activity relationships, and in vitro and in vivo characterization of a novel series of Na(V)1.7 inhibitors based on the oxoisoindoline core. Extensive studies with focus on optimization of Na(V)1.7 potency, selectivity over Na(V)1.5, and metabolic stability properties produced several interesting oxoisoindoline carboxamides (16A, 26B, 28, 51, 60, and 62) that were further characterized. The oxoisoindoline carboxamides interacted with the local anesthetics binding site. In spite of this, several compounds showed functional selectivity versus Na(V)1.5 of more than 100-fold. This appeared to be a combination of subtype and state-dependent selectivity. Compound 28 showed concentration-dependent inhibition of nerve injury-induced ectopic in an ex vivo DRG preparation from SNL rats. Compounds 16A and 26B demonstrated concentration-dependent efficacy in preclinical behavioral pain models. The oxoisoindoline carboxamides series described here may be valuable for further investigations for pain therapeutics.
Assuntos
Amidas/síntese química , Analgésicos/síntese química , Isoindóis/síntese química , Dor/tratamento farmacológico , Bloqueadores dos Canais de Sódio/síntese química , Canais de Sódio/fisiologia , Amidas/farmacocinética , Amidas/farmacologia , Analgésicos/farmacocinética , Analgésicos/farmacologia , Animais , Artrite Experimental/tratamento farmacológico , Artrite Experimental/etiologia , Células CHO , Carragenina , Dor Crônica/tratamento farmacológico , Dor Crônica/etiologia , Cricetinae , Cricetulus , Células HEK293 , Humanos , Isoindóis/farmacocinética , Isoindóis/farmacologia , Masculino , Microssomos Hepáticos/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.7 , Dor/etiologia , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley , Bloqueadores dos Canais de Sódio/farmacocinética , Bloqueadores dos Canais de Sódio/farmacologia , Solubilidade , Nervos Espinhais/lesões , Relação Estrutura-AtividadeRESUMO
Efficient aerobic oxidation of alcohols was developed via a biomimetic catalytic system. The principle for this aerobic oxidation is reminiscent of biological oxidation of alcohols via the respiratory chain and involves selective electron/proton transfer. A substrate-selective catalyst (ruthenium complex 1) dehydrogenates the alcohol, and the hydrogens abstracted are transferred to an electron-rich quinone (4b). The hydroquinone thus formed is continuously reoxidized by air with the aid of an oxygen-activating Co[bond]salen type complex (6). Most alcohols are oxidized to ketones in high yield and selectivity within 1-2 h, and the catalytic system tolerates a wide range of O(2) concentrations without being deactivated. Compared to other ruthenium-catalyzed aerobic oxidations this new catalytic system has high turnover frequency (TOF).