RESUMO
We previously reported the small organic N-type calcium channel blocker NP078585 that while efficacious in animal models for pain, exhibited modest L-type calcium channel selectivity and substantial off-target inhibition against the hERG potassium channel. Structure-activity studies to optimize NP078585 preclinical properties resulted in compound 16, which maintained high potency for N-type calcium channel blockade, and possessed excellent selectivity over the hERG (~120-fold) and L-type (~3600-fold) channels. Compound 16 shows significant anti-hyperalgesic activity in the spinal nerve ligation model of neuropathic pain and is also efficacious in the rat formalin model of inflammatory pain.
Assuntos
Analgésicos/síntese química , Bloqueadores dos Canais de Cálcio/síntese química , Canais de Cálcio Tipo N/metabolismo , Hiperalgesia/tratamento farmacológico , Neuralgia/tratamento farmacológico , Piperazinas/síntese química , Nervos Espinhais/efeitos dos fármacos , Analgésicos/farmacologia , Animais , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo L/metabolismo , Modelos Animais de Doenças , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/metabolismo , Hiperalgesia/metabolismo , Neuralgia/metabolismo , Piperazinas/farmacologia , Ratos , Ratos Sprague-Dawley , Nervos Espinhais/metabolismo , Relação Estrutura-AtividadeRESUMO
A novel series of compounds derived from the previously reported N-type calcium channel blocker NP118809 (1-(4-benzhydrylpiperazin-1-yl)-3,3-diphenylpropan-1-one) is described. Extensive SAR studies resulted in compounds with IC(50) values in the range of 10-150 nM and selectivity over the L-type channels up to nearly 1200-fold. Orally administered compounds 5 and 21 exhibited both anti-allodynic and anti-hyperalgesic activity in the spinal nerve ligation model of neuropathic pain.
Assuntos
Compostos Benzidrílicos/síntese química , Bloqueadores dos Canais de Cálcio/síntese química , Canais de Cálcio Tipo N/efeitos dos fármacos , Piperazinas/síntese química , Administração Oral , Analgésicos/síntese química , Analgésicos/química , Analgésicos/farmacologia , Animais , Compostos Benzidrílicos/química , Compostos Benzidrílicos/farmacologia , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacologia , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Piperazinas/química , Piperazinas/farmacologia , Ratos , Ratos Sprague-Dawley , Solubilidade , Relação Estrutura-Atividade , Água/químicaRESUMO
The therapeutic agents flunarizine and lomerizine exhibit inhibitory activities against a variety of ion channels and neurotransmitter receptors. We have optimized their scaffolds to obtain more selective N-type calcium channel blockers. During this optimization, we discovered NP118809 and NP078585, two potent N-type calcium channel blockers which have good selectivity over L-type calcium channels. Upon intraperitoneal administration both compounds exhibit analgesic activity in a rodent model of inflammatory pain. NP118809 further exhibits a number of favorable preclinical characteristics as they relate to overall pharmacokinetics and minimal off-target activity including the hERG potassium channel.
