RESUMO
Voltage-gated sodium channel NaV1.7 is a genetically validated target for pain. Identification of NaV1.7 inhibitors with all of the desired properties to develop as an oral therapeutic for pain has been a major challenge. Herein, we report systematic structure-activity relationship (SAR) studies carried out to identify novel sulfonamide derivatives as potent, selective, and state-dependent NaV1.7 inhibitors for pain. Scaffold hopping from benzoxazine to chroman and indane bicyclic system followed by thiazole replacement on sulfonamide led to identification of lead molecules with significant improvement in solubility, selectivity over NaV1.5, and CYP2C9 inhibition. The lead molecules 13, 29, 32, 43, and 51 showed a favorable pharmacokinetics (PK) profile across different species and robust efficacy in veratridine and formalin-induced inflammatory pain models in mice. Compound 51 also showed significant effects on the CCI-induced neuropathic pain model. The profile of 51 indicated that it has the potential for further evaluation as a therapeutic for pain.
Assuntos
Cromanos/química , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Sulfonamidas/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/química , Animais , Cromanos/farmacocinética , Cromanos/uso terapêutico , Citocromo P-450 CYP2C9/química , Citocromo P-450 CYP2C9/metabolismo , Citocromo P-450 CYP3A/química , Citocromo P-450 CYP3A/metabolismo , Modelos Animais de Doenças , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Canal de Sódio Disparado por Voltagem NAV1.7/química , Neuralgia/induzido quimicamente , Neuralgia/tratamento farmacológico , Neuralgia/patologia , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapêutico , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacocinética , Bloqueadores do Canal de Sódio Disparado por Voltagem/uso terapêuticoRESUMO
Acute pruritus occurs in various disorders. Despite severe repercussions on quality of life treatment options remain limited. Voltage-gated sodium channels (NaV) are indispensable for transformation and propagation of sensory signals implicating them as drug targets. Here, NaV1.7, 1.8 and 1.9 were compared for their contribution to itch by analysing NaV-specific knockout mice. Acute pruritus was induced by a comprehensive panel of pruritogens (C48/80, endothelin, 5-HT, chloroquine, histamine, lysophosphatidic acid, trypsin, SLIGRL, ß-alanine, BAM8-22), and scratching was assessed using a magnet-based recording technology. We report an unexpected stimulus-dependent diversity in NaV channel-mediated itch signalling. NaV1.7-/- showed substantial scratch reduction mainly towards strong pruritogens. NaV1.8-/- impaired histamine and 5-HT-induced scratching while NaV1.9 was involved in itch signalling towards 5-HT, C48/80 and SLIGRL. Furthermore, similar microfluorimetric calcium responses of sensory neurons and expression of itch-related TRP channels suggest no change in sensory transduction but in action potential transformation and conduction. The cumulative sum of scratching over all pruritogens confirmed a leading role of NaV1.7 and indicated an overall contribution of NaV1.9. Beside the proposed general role of NaV1.7 and 1.9 in itch signalling, scrutiny of time courses suggested NaV1.8 to sustain prolonged itching. Therefore, NaV1.7 and 1.9 may represent targets in pruritus therapy.
Assuntos
Histamina/toxicidade , Canal de Sódio Disparado por Voltagem NAV1.7/fisiologia , Canal de Sódio Disparado por Voltagem NAV1.8/fisiologia , Canal de Sódio Disparado por Voltagem NAV1.9/fisiologia , Prurido/prevenção & controle , Animais , Camundongos , Camundongos Knockout , Canal de Sódio Disparado por Voltagem NAV1.7/química , Canal de Sódio Disparado por Voltagem NAV1.8/química , Canal de Sódio Disparado por Voltagem NAV1.9/química , Prurido/induzido quimicamente , Prurido/patologia , Transdução de SinaisRESUMO
3-Aryl-indole and 3-aryl-indazole derivatives were identified as potent and selective Nav1.7 inhibitors. Compound 29 was shown to be efficacious in the mouse formalin assay and also reduced complete Freund's adjuvant (CFA)-induced thermal hyperalgesia and chronic constriction injury (CCI) induced cold allodynia and models of inflammatory and neuropathic pain, respectively, following intraperitoneal (IP) doses of 30 mg/kg. The observed efficacy could be correlated with the mouse dorsal root ganglion exposure and NaV1.7 potency associated with 29.
Assuntos
Indazóis/química , Indóis/química , Canal de Sódio Disparado por Voltagem NAV1.7/química , Neuralgia/tratamento farmacológico , Sulfonamidas/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/uso terapêutico , Animais , Avaliação Pré-Clínica de Medicamentos , Células HEK293 , Meia-Vida , Humanos , Hiperalgesia/tratamento farmacológico , Hiperalgesia/patologia , Masculino , Camundongos , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Neuralgia/patologia , Técnicas de Patch-Clamp , Relação Estrutura-Atividade , Sulfonamidas/metabolismo , Sulfonamidas/uso terapêutico , Bloqueadores do Canal de Sódio Disparado por Voltagem/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/metabolismoRESUMO
hNav1.7 receives a lot of attention owing to its attractive mechanism of action in pain processing pathway. We have previously reported our design of a novel series of tetrahydropyridine analogues towards hNav1.7 selective inhibitors. Herein, we disclose further efforts to the optimization of hit compound (-)-6, which led to the identification of aminocyclohexene analogues (-)-9 and (-)-17 with good potency, high selectivity, and minimal CYP inhibition. Both compounds (-)-9 and (-)-17 demonstrated improved pharmacokinetic profiles in rats, and robust efficacy in rat formalin-induced nociception and spinal nerve ligation (SNL) models.
Assuntos
Analgésicos/química , Cicloexenos/química , Canal de Sódio Disparado por Voltagem NAV1.7/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/química , Administração Oral , Analgésicos/farmacocinética , Analgésicos/uso terapêutico , Animais , Sítios de Ligação , Cicloexenos/farmacocinética , Cicloexenos/uso terapêutico , Citocromo P-450 CYP2C9/química , Citocromo P-450 CYP2C9/metabolismo , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Dor/tratamento farmacológico , Estrutura Terciária de Proteína , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacocinética , Bloqueadores do Canal de Sódio Disparado por Voltagem/uso terapêuticoRESUMO
The voltage-gated sodium channel Nav1.7 is a genetically validated target for the treatment of pain with gain-of-function mutations in man eliciting a variety of painful disorders and loss-of-function mutations affording insensitivity to pain. Unfortunately, drugs thought to garner efficacy via Nav1 inhibition have undesirable side effect profiles due to their lack of selectivity over channel isoforms. Herein we report the discovery of a novel series of orally bioavailable arylsulfonamide Nav1.7 inhibitors with high levels of selectivity over Nav1.5, the Nav isoform responsible for cardiovascular side effects, through judicious use of parallel medicinal chemistry and physicochemical property optimization. This effort produced inhibitors such as compound 5 with excellent potency, selectivity, behavioral efficacy in a rodent pain model, and efficacy in a mouse itch model suggestive of target modulation.