RESUMO
Structural modifications of the neuronal calcium channel blocker MONIRO-1, including constraining the phenoxyaniline portion of the molecule and replacing the guanidinium functionality with tertiary amines, led to compounds with significantly improved affinities for the endogenously expressed CaV2.2 channel in the SH-SY5Y neuroblastoma cell line. These analogues also showed promising activity towards the CaV3.2 channel, recombinantly expressed in HEK293T cells. Both of these ion channels have received attention as likely targets for the treatment of neuropathic pain. The dibenzoazepine and dihydrobenzodiazepine derivatives prepared in this study show an encouraging combination of neuronal calcium ion channel inhibitory potency, plasma stability and potential to cross the blood-brain-barrier.
Assuntos
Anilidas/síntese química , Antineoplásicos/síntese química , Benzodiazepinas/química , Bloqueadores dos Canais de Cálcio/síntese química , Canais de Cálcio/metabolismo , Neuralgia/tratamento farmacológico , Proteínas Recombinantes/metabolismo , Anilidas/metabolismo , Animais , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Barreira Hematoencefálica/metabolismo , Cálcio/metabolismo , Bloqueadores dos Canais de Cálcio/metabolismo , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio/genética , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Neurônios/metabolismo , Ratos Sprague-Dawley , Proteínas Recombinantes/genética , Transdução de Sinais , Relação Estrutura-AtividadeRESUMO
Both N- and T-type calcium ion channels have been implicated in pain transmission and the N-type channel is a well-validated target for the treatment of neuropathic pain. An SAR investigation of a series of substituted aminobenzothiazoles identified a subset of five compounds with comparable activity to the positive control Z160 in a FLIPR-based intracellular calcium response assay measuring potency at both CaV2.2 and CaV3.2 channels. These compounds may form the basis for the development of drug leads and tool compounds for assessing in vivo effects of variable modulation of CaV2.2 and CaV3.2 channels.
Assuntos
Benzimidazóis/síntese química , Benzotiazóis/síntese química , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo N/química , Canais de Cálcio Tipo T/química , Ciclopropanos/síntese química , Naftalenos/síntese química , Piperidinas/síntese química , Benzimidazóis/química , Benzimidazóis/farmacologia , Benzotiazóis/química , Benzotiazóis/farmacologia , Bloqueadores dos Canais de Cálcio/síntese química , Bloqueadores dos Canais de Cálcio/química , Canais de Cálcio Tipo N/efeitos dos fármacos , Canais de Cálcio Tipo T/efeitos dos fármacos , Ciclopropanos/química , Ciclopropanos/farmacologia , Estrutura Molecular , Naftalenos/química , Naftalenos/farmacologia , Piperazinas/síntese química , Piperazinas/química , Piperazinas/farmacologia , Piperidinas/química , Piperidinas/farmacologia , Relação Estrutura-AtividadeRESUMO
Building on previous investigations, structural modifications to the neuronal calcium ion channel blocker MONIRO-1 and related compounds were conducted that included replacement of the amide linker with an aniline and isosteric sulfonamide moiety, and the previously used strategy of substitution of the guanidinium group with less hydrophilic amine functionalities. A comprehensive SAR study revealed a number of phenoxyaniline and sulfonamide compounds that were more potent or had similar potency for the CaV2.2 and CaV3.2 channel compared to MONIRO-1 when evaluated in a FLIPR-based intracellular calcium response assay. Cytotoxicity investigations indicated that the sulfonamide analogues were well tolerated by Cos-7 cells at dosages required to inhibit both calcium ion channels. The sulfonamide derivatives were the most promising CaV2.2 inhibitors developed by us to date due, possessing high stability in plasma, low toxicity (estimated therapeutic index > 10), favourable CNS MPO scores (4.0-4.4) and high potency and selectivity, thereby, making this class of compounds suitable candidates for future in vivo studies.