RESUMO
Dysfunction of voltage-gated sodium channel Nav1.2 causes various epileptic disorders, and inhibition of the channel has emerged as an attractive therapeutic strategy. However, currently available Nav1.2 inhibitors exhibit low potency and limited structural diversity. In this study, a novel series of pyrimidine-based derivatives with Nav1.2 inhibitory activity were designed, synthesized, and evaluated. Compounds 14 and 35 exhibited potent activity against Nav1.2, boasting IC50 values of 120 and 65 nM, respectively. Compound 14 displayed favorable pharmacokinetics (F = 43%) following intraperitoneal injection and excellent brain penetration potency (B/P = 3.6). Compounds 14 and 35 exhibited robust antiepileptic activities in the maximal electroshock test, with ED50 values of 3.2 and 11.1 mg/kg, respectively. Compound 35 also demonstrated potent antiepileptic activity in a 6 Hz (32 mA) model, with an ED50 value of 18.5 mg/kg. Overall, compounds 14 and 35 are promising leads for the development of new small-molecule therapeutics for epilepsy.
Assuntos
Anticonvulsivantes , Epilepsia , Canal de Sódio Disparado por Voltagem NAV1.2 , Pirimidinas , Animais , Pirimidinas/farmacologia , Pirimidinas/química , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Pirimidinas/uso terapêutico , Anticonvulsivantes/farmacologia , Anticonvulsivantes/química , Anticonvulsivantes/síntese química , Anticonvulsivantes/uso terapêutico , Anticonvulsivantes/farmacocinética , Epilepsia/tratamento farmacológico , Epilepsia/metabolismo , Camundongos , Canal de Sódio Disparado por Voltagem NAV1.2/metabolismo , Relação Estrutura-Atividade , Humanos , Modelos Animais de Doenças , Masculino , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Bloqueadores do Canal de Sódio Disparado por Voltagem/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/síntese química , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacocinética , Bloqueadores do Canal de Sódio Disparado por Voltagem/uso terapêutico , Descoberta de Drogas , Eletrochoque , Simulação de Acoplamento MolecularRESUMO
Chronic pain is a common and challenging clinical problem that significantly impacts patients' quality of life. The sodium channel Nav1.8 plays a crucial role in the occurrence and development of chronic pain, making it one of the key targets for treating chronic pain. In this article, we combined virtual screening with cell membrane chromatography techniques to establish a novel method for rapid high-throughput screening of selective Nav1.8 inhibitors. Using this approach, we identified a small molecule compound 6, which not only demonstrated high affinity and inhibitory activity against Nav1.8 but also exhibited significant inhibitory effects on CFA-induced chronic inflammatory pain. Compared to the positive drug VX-150, compound 6 showed a more prolonged analgesic effect, making it a promising candidate as a Nav1.8 inhibitor with potential clinical applications. This discovery provides a new therapeutic option for the treatment of chronic pain.
Assuntos
Analgésicos , Canal de Sódio Disparado por Voltagem NAV1.8 , Sulfonamidas , Analgésicos/farmacologia , Analgésicos/química , Analgésicos/síntese química , Sulfonamidas/química , Sulfonamidas/farmacologia , Sulfonamidas/síntese química , Animais , Humanos , Canal de Sódio Disparado por Voltagem NAV1.8/metabolismo , Relação Estrutura-Atividade , Benzenossulfonamidas , Estrutura Molecular , Camundongos , Relação Dose-Resposta a Droga , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Bloqueadores do Canal de Sódio Disparado por Voltagem/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/síntese químicaRESUMO
Diterpenoid alkaloids, originating from the amination of natural tetracyclic diterpenes, have long interested scientists due to their medicinal uses and infamous toxicity which has limited the clinical application of the native compound. Alkaloid lappaconitine extracted from various Aconitum and Delphinium species has displayed extensive bioactivities and active ongoing research to reduce its adverse effects. A convenient route to construct hybrid molecules containing diterpenoid alkaloid lappaconitine and 3H-1,5-benzodiazepine fragments was proposed. The key stage involved the formation of 5'-alkynone-lappaconitines in situ by acyl Sonogashira coupling of 5'-ethynyllappaconitine, followed by cyclocondensation with o-phenylenediamine. New hybrid compounds showed low toxicity and outstanding analgesic activity in experimental pain models, which depended on the nature of the substituent in the benzodiazepine nucleus. An analogous dependence was also shown for the antiarrhythmic activity in the epinephrine arrhythmia test in vivo. Studies on the isolated atrium have shown that the mechanism of action of the new compounds is included the blockade of beta-adrenergic receptors and potassium channels. Molecular docking analysis was conducted to determine the binding potential of target molecules with the voltage-gated sodium channel NaV1.5. All obtained results provide a basis for future rational modifications of lappaconitine, reducing side effects, while retaining its therapeutic effects.
Assuntos
Aconitina , Analgésicos não Narcóticos , Antiarrítmicos , Benzodiazepinas , Bloqueadores do Canal de Sódio Disparado por Voltagem , Aconitina/análogos & derivados , Aconitina/síntese química , Aconitina/farmacologia , Benzodiazepinas/síntese química , Benzodiazepinas/química , Benzodiazepinas/farmacologia , Modelos Moleculares , Analgésicos não Narcóticos/síntese química , Analgésicos não Narcóticos/química , Analgésicos não Narcóticos/farmacologia , Ligação Proteica , Animais , Ratos , Ratos Wistar , Antiarrítmicos/síntese química , Antiarrítmicos/química , Antiarrítmicos/farmacologia , Canal de Sódio Disparado por Voltagem NAV1.5 , Masculino , Camundongos , Camundongos Endogâmicos , Bloqueadores do Canal de Sódio Disparado por Voltagem/síntese química , Bloqueadores do Canal de Sódio Disparado por Voltagem/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Simulação de Acoplamento MolecularRESUMO
Tetrodotoxin (TTX) is a neurotoxic natural product that is an indispensable probe in neuroscience, a biosynthetic and ecological enigma, and a celebrated target of synthetic chemistry. Here, we present a stereoselective synthesis of TTX that proceeds in 22 steps from a glucose derivative. The central cyclohexane ring of TTX and its α-tertiary amine moiety were established by the intramolecular 1,3-dipolar cycloaddition of a nitrile oxide, followed by alkynyl addition to the resultant isoxazoline. A ruthenium-catalyzed hydroxylactonization set the stage for the formation of the dioxa-adamantane core. Installation of the guanidine, oxidation of a primary alcohol, and a late-stage epimerization gave a mixture of TTX and anhydro-TTX. This synthetic approach could give ready access to biologically active derivatives.
Assuntos
Tetrodotoxina , Bloqueadores do Canal de Sódio Disparado por Voltagem , Catálise , Reação de Cicloadição , Guanidina/química , Rutênio/química , Estereoisomerismo , Tetrodotoxina/síntese química , Bloqueadores do Canal de Sódio Disparado por Voltagem/síntese químicaRESUMO
Three analogues of To042, a tocainide-related lead compound recently reported for the treatment of myotonia, were synthesized and evaluated inâ vitro as skeletal muscle sodium channel blockers possibly endowed with enhanced use-dependent behavior. Patch-clamp experiments on hNav1.4 expressed in HEK293 cells showed that N-[(naphthalen-1-yl)methyl]-4-[(2,6-dimethyl)phenoxy]butan-2-amine, the aryloxyalkyl bioisostere of To042, exerted a higher use-dependent block than To042 thus being able to preferentially block the channels in over-excited membranes while preserving healthy tissue function. It also showed the lowest active transport across BBB according to the results of P-glycoprotein (P-gp) interacting activity evaluation and the highest cytoprotective effect on HeLa cells. Quantum mechanical calculations and dockings gave insights on the most probable conformation of the aryloxyalkyl bioisostere of To042 in solution and the target residues involved in the binding, respectively. Both approaches indicated the conformations that might be adopted in both the unbound and bound state of the ligand. Overall, N-[(naphthalen-1-yl)methyl]-4-[(2,6-dimethyl)phenoxy]butan-2-amine exhibits an interesting toxico-pharmacological profile and deserves further investigation.
Assuntos
Butilaminas/farmacologia , Canal de Sódio Disparado por Voltagem NAV1.4/metabolismo , Éteres Fenílicos/farmacologia , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Antioxidantes/síntese química , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Antioxidantes/toxicidade , Butilaminas/síntese química , Butilaminas/metabolismo , Butilaminas/toxicidade , Células HEK293 , Células HeLa , Humanos , Mexiletina/farmacologia , Simulação de Acoplamento Molecular , Éteres Fenílicos/síntese química , Éteres Fenílicos/metabolismo , Éteres Fenílicos/toxicidade , Ligação Proteica , Espécies Reativas de Oxigênio/metabolismo , Bloqueadores do Canal de Sódio Disparado por Voltagem/síntese química , Bloqueadores do Canal de Sódio Disparado por Voltagem/metabolismo , Bloqueadores do Canal de Sódio Disparado por Voltagem/toxicidadeRESUMO
Under the hypothesis that cardioprotective agents might benefit from synergism between antiarrhythmic activity and antioxidant properties, a small series of mexiletine analogues were coupled with the 2,2,5,5-tetramethylpyrroline moiety, known for its antioxidant effect, in order to obtain dual-acting drugs potentially useful in the protection of the heart against post-ischemic reperfusion injury. The pyrroline derivatives reported herein were found to be more potent as antiarrhythmic agents than mexiletine and displayed antioxidant activity. The most interesting tetramethylpyrroline congener, a tert-butyl-substituted analogue, was at least 100 times more active as an antiarrhythmic than mexiletine.
Assuntos
Antiarrítmicos/farmacologia , Antioxidantes/farmacologia , Pirróis/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Canais de Sódio Disparados por Voltagem/metabolismo , Animais , Antiarrítmicos/síntese química , Antiarrítmicos/química , Antioxidantes/síntese química , Antioxidantes/química , Teoria da Densidade Funcional , Fluoresceínas/metabolismo , Cobaias , Humanos , Estrutura Molecular , Pirróis/síntese química , Pirróis/química , Traumatismo por Reperfusão/metabolismo , Células Tumorais Cultivadas , Bloqueadores do Canal de Sódio Disparado por Voltagem/síntese química , Bloqueadores do Canal de Sódio Disparado por Voltagem/químicaRESUMO
Voltage-gated sodium (NaV) channels are pore-forming transmembrane proteins that play essential roles in excitable cells, and they are key targets for antiepileptic, antiarrhythmic, and analgesic drugs. We implemented a heterobivalent design strategy to modulate the potency, selectivity, and binding kinetics of NaV channel ligands. We conjugated µ-conotoxin KIIIA, which occludes the pore of the NaV channels, to an analogue of huwentoxin-IV, a spider-venom peptide that allosterically modulates channel gating. Bioorthogonal hydrazide and copper-assisted azide-alkyne cycloaddition conjugation chemistries were employed to generate heterobivalent ligands using polyethylene glycol linkers spanning 40-120 Å. The ligand with an 80 Å linker had the most pronounced bivalent effects, with a significantly slower dissociation rate and 4-24-fold higher potency compared to those of the monovalent peptides for the human NaV1.4 channel. This study highlights the power of heterobivalent ligand design and expands the repertoire of pharmacological probes for exploring the function of NaV channels.
Assuntos
Ligantes , Canal de Sódio Disparado por Voltagem NAV1.4/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Bloqueadores do Canal de Sódio Disparado por Voltagem/química , Potenciais de Ação/efeitos dos fármacos , Sequência de Aminoácidos , Animais , Sítios de Ligação , Conotoxinas/química , Conotoxinas/metabolismo , Reação de Cicloadição , Humanos , Concentração Inibidora 50 , Cinética , Simulação de Acoplamento Molecular , Canal de Sódio Disparado por Voltagem NAV1.4/química , Canal de Sódio Disparado por Voltagem NAV1.7/química , Técnicas de Patch-Clamp , Polietilenos/química , Venenos de Aranha/síntese química , Venenos de Aranha/química , Venenos de Aranha/metabolismo , Aranhas/metabolismo , Bloqueadores do Canal de Sódio Disparado por Voltagem/síntese química , Bloqueadores do Canal de Sódio Disparado por Voltagem/metabolismo , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologiaRESUMO
The discovery of a novel class of state-dependent voltage-gated sodium channel (NaV)1.7 inhibitors is described. By the modification of amide or urethane bond in NaV1.7 blocker III, structure-activity relationship studies that led to the identification of novel NaV1.7 inhibitor 2i (DS01171986) were performed. Compound 2i exhibited state-dependent inhibition of NaV1.7 without NaV1.1, NaV1.5 or human ether-a-go-go related gene (hERG) liabilities at concentrations up to 100 µM. Further biological profiling successfully revealed that 2i possessed potent analgesic properties in a murine model of neuropathic pain (ED50: 3.4 mg/kg) with an excellent central nervous system (CNS) safety margin (> 600 fold).
Assuntos
Descoberta de Drogas , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Neuralgia/tratamento farmacológico , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Animais , Relação Dose-Resposta a Droga , Humanos , Masculino , Camundongos , Estrutura Molecular , Neuralgia/metabolismo , Relação Estrutura-Atividade , Bloqueadores do Canal de Sódio Disparado por Voltagem/síntese química , Bloqueadores do Canal de Sódio Disparado por Voltagem/químicaRESUMO
A highly potent, selective NaV1.7 inhibitor, DS-1971a, has been discovered. Exploration of the left-hand phenyl ring of sulfonamide derivatives (I and II) led to the discovery of novel series of cycloalkane derivatives with high NaV1.7 inhibitory potency in vitro. As the right-hand heteroaromatic ring affected the mechanism-based inhibition liability of CYP3A4, replacement of this moiety resulted in the generation of 4-pyrimidyl derivatives. Additionally, GSH adducts formation, which can cause idiosyncratic drug toxicity, was successfully avoided by this modification. An additional optimization led to the discovery of DS-1971a. In preclinical studies, DS-1971a demonstrated highly potent selective in vitro profile with robust efficacy in vivo. DS-1971a exhibited a favorable toxicological profile, which enabled multiple-dose studies of up to 600 mg bid or 400 mg tid (1200 mg/day) administered for 14 days to healthy human males. DS-1971a is expected to exert potent efficacy in patients with peripheral neuropathic pain, with a favorable safety profile.
Assuntos
Analgésicos/uso terapêutico , Hiperalgesia/tratamento farmacológico , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Bloqueadores do Canal de Sódio Disparado por Voltagem/uso terapêutico , Analgésicos/síntese química , Analgésicos/toxicidade , Animais , Descoberta de Drogas , Feminino , Humanos , Macaca fascicularis , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/toxicidade , Pirimidinas/síntese química , Pirimidinas/toxicidade , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/toxicidade , Bloqueadores do Canal de Sódio Disparado por Voltagem/síntese química , Bloqueadores do Canal de Sódio Disparado por Voltagem/toxicidadeRESUMO
We previously reported that a lipophilic N-(4'-hydroxy-3',5'-di-tert-butylbenzyl) derivative (1) of the voltage-gated sodium channel blocker mexiletine, was a more potent sodium channel blocker inâ vitro and inâ vivo. We demonstrate that replacing the chiral methylethylene linker between the amine and di-tert-butylphenol with an achiral 1,3-propylene linker (to give (2)) maintains potency inâ vitro. We synthesized 25 analogues bearing the 1,3-propylene linker and found that minor structural changes resulted in pronounced changes in state dependence of blocking human NaV 1.2 and 1.6 channels by high-throughput patch-clamp analysis. Compared to mexiletine, compounds 1 and 2 are highly selective NaV 1.2 inhibitors and >500 times less potent in inhibiting NaV 1.6 channels. On the other hand, a derivative (compound 4) bearing 2,6-dimethoxy groups in place of the 2,6-dimethyl groups found in mexiletine was found to be the most potent inhibitor, but is nonselective against both channels in the tonic, frequency-dependent and inactivated states. In a kindled mouse model of refractory epilepsy, compound 2 inhibited seizures induced by 6â Hz 44â mA electrical stimulation with an IC50 value of 49.9±1.6â mg kg-1 . As established sodium channel blockers do not suppress seizures in this mouse model, this indicates that 2 could be a promising candidate for treating pharmaco-resistant epilepsy.
Assuntos
Benzilaminas/síntese química , Convulsões/tratamento farmacológico , Bloqueadores do Canal de Sódio Disparado por Voltagem/síntese química , Canais de Sódio Disparados por Voltagem/metabolismo , Animais , Benzilaminas/metabolismo , Estabilidade de Medicamentos , Estimulação Elétrica , Humanos , Mexiletina/metabolismo , Camundongos , Estrutura Molecular , Técnicas de Patch-Clamp/métodos , Relação Estrutura-Atividade , Bloqueadores do Canal de Sódio Disparado por Voltagem/metabolismoRESUMO
The voltage gated sodium channel NaV1.8 has been postulated to play a key role in the transmission of pain signals. Core hopping from our previously reported phenylimidazole leads has allowed the identification of a novel series of benzimidazole NaV1.8 blockers. Subsequent optimization allowed the identification of compound 9, PF-06305591, as a potent, highly selective blocker with an excellent preclinical in vitro ADME and safety profile.
Assuntos
Benzimidazóis/farmacologia , Canal de Sódio Disparado por Voltagem NAV1.8/metabolismo , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Benzimidazóis/síntese química , Benzimidazóis/química , Benzimidazóis/farmacocinética , Desenho de Fármacos , Células HEK293 , Humanos , Estrutura Molecular , Solubilidade , Relação Estrutura-Atividade , Bloqueadores do Canal de Sódio Disparado por Voltagem/síntese química , Bloqueadores do Canal de Sódio Disparado por Voltagem/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacocinéticaRESUMO
Voltage-gated sodium channels (NaVs) are membrane proteins that are involved in the generation and propagation of action potentials in neurons. Recently, the structure of a complex made of a tetrodotoxin-sensitive (TTX-s) NaV subtype with saxitoxin (STX), a shellfish toxin, was determined. STX potently inhibits TTX-s NaV, and is used as a biological tool to investigate the function of NaVs. More than 50 analogs of STX have been isolated from nature. Among them, zetekitoxin AB (ZTX) has a distinctive chemical structure, and is the most potent inhibitor of NaVs, including tetrodotoxin-resistant (TTX-r) NaV. Despite intensive synthetic studies, total synthesis of ZTX has not yet been achieved. Here, we review recent efforts directed toward the total synthesis of ZTX, including syntheses of 11-saxitoxinethanoic acid (SEA), which is considered a useful synthetic model for ZTX, since it contains a key carbon-carbon bond at the C11 position.
Assuntos
Saxitoxina/análogos & derivados , Bloqueadores do Canal de Sódio Disparado por Voltagem/síntese química , Animais , Saxitoxina/síntese química , Saxitoxina/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/químicaRESUMO
Voltage-gated sodium channels (VGSC) are a well-established drug target for anti-epileptic, anti-arrhythmic and pain medications due to their presence and the important roles that they play in excitable cells. Recently, their presence has been recognized in non-excitable cells such as cancer cells and their overexpression has been shown to be associated with metastatic behavior in a variety of human cancers. The neonatal isoform of the VGSC subtype, Nav1.5 (nNav1.5) is overexpressed in the highly aggressive human breast cancer cell line, MDA-MB-231. The activity of nNav1.5 is known to promote the breast cancer cell invasion in vitro and metastasis in vivo, and its expression in primary mammary tumors has been associated with metastasis and patient death. Metastasis development is responsible for the high mortality of breast cancer and currently there is no treatment available to specifically prevent or inhibit breast cancer metastasis. In the present study, a 3D-QSAR model is used to assist the development of low micromolar small molecule VGSC blockers. Using this model, we have designed, synthesized and evaluated five small molecule compounds as blockers of nNav1.5-dependent inward currents in whole-cell patch-clamp experiments in MDA-MB-231 cells. The most active compound identified from these studies blocked sodium currents by 34.9⯱â¯6.6% at 1⯵M. This compound also inhibited the invasion of MDA-MB-231 cells by 30.3⯱â¯4.5% at 1⯵M concentration without affecting the cell viability. The potent small molecule compounds presented here have the potential to be developed as drugs for breast cancer metastasis treatment.
Assuntos
Antineoplásicos/farmacologia , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Invasividade Neoplásica/prevenção & controle , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Desenho de Fármacos , Humanos , Metástase Neoplásica/prevenção & controle , Relação Quantitativa Estrutura-Atividade , Bloqueadores do Canal de Sódio Disparado por Voltagem/síntese química , Bloqueadores do Canal de Sódio Disparado por Voltagem/químicaRESUMO
A series of (E)-3-(benzo[d][1,3]dioxol-5-ylmethylene)pyrrolidin-2-one derivatives were designed, synthesized, and evaluated for their anticonvulsant activities. In the preliminary screening, compounds 5, 6a-6f and 6h-6i showed promising anticonvulsant activities in MES model, while 6f and 6g represented protection against seizures at doses of 100â¯mg/kg and 0.5â¯h in scPTZ model. The most active compound 6d had a high-degree protection against the MES-induced seizures with ED50 value of 4.3â¯mg/kg and TD50 value of 160.9â¯mg/kg after intraperitoneal (i.p.) injection in mice, which provided 6d in a high protective index (TD50/ED50) of 37.4 comparable to the reference drugs. Beyond that, 6d has been selected and evaluated in vitro experiment to estimate the activation impact. Apparently, 6d clearly inhibits the Nav1.1 channel. Our preliminary results provide new insights for the development of small-molecule activators targeting specifically Nav1.1 channels to design potential drugs for treating epilepsy. The computational parameters, such as homology modeling, docking study, and ADME prediction, were made to exploit the results.
Assuntos
Anticonvulsivantes/farmacologia , Benzodioxóis/farmacologia , Pirrolidinonas/farmacologia , Animais , Anticonvulsivantes/síntese química , Anticonvulsivantes/química , Benzodioxóis/síntese química , Benzodioxóis/química , Sítios de Ligação , Células CHO , Cricetulus , Desenho de Fármacos , Electrophorus , Humanos , Masculino , Camundongos , Simulação de Acoplamento Molecular , Canal de Sódio Disparado por Voltagem NAV1.1/química , Canal de Sódio Disparado por Voltagem NAV1.1/metabolismo , Fenobarbital/farmacologia , Fenitoína/farmacologia , Pirrolidinonas/síntese química , Pirrolidinonas/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/síntese química , Bloqueadores do Canal de Sódio Disparado por Voltagem/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologiaRESUMO
Tocainide is an antiarrhythmic agent belonging to class IB that was primarily used for suppression of symptomatic ventricular arrhythmias. Tocainide was also reported to relieve pain such as tic douloureux, trigemina neuralgia in humans and tinnitus. Significant antinociception, as assayed on the hot-plate test, was observed after intraperitoneal injection of tocainide, too. By the mid-1980s tocainide was emerging as a more consistently effective treatment for myotonic disorders. Numerous reports of serious adverse reactions led to the use of tocainide being discontinued, even though research on tocainide and its analogues, endowed with a better pharmacological profile, is still in progress for their potential usefulness in the treatment of myotonias. This review is focused on the description of the different synthetic routes to racemic and optically active tocainide developed in the last decades, as well as analytical studies regarding enantioseparation methods. Finally, some analogues of tocainide reported in the literature, most of which with pharmacological studies, have been mentioned.
Assuntos
Antiarrítmicos/síntese química , Tocainide/análogos & derivados , Antiarrítmicos/farmacocinética , Antiarrítmicos/uso terapêutico , Arritmias Cardíacas/tratamento farmacológico , Meia-Vida , Humanos , Canal de Sódio Disparado por Voltagem NAV1.4/química , Canal de Sódio Disparado por Voltagem NAV1.4/metabolismo , Relação Quantitativa Estrutura-Atividade , Tocainide/farmacocinética , Tocainide/uso terapêutico , Bloqueadores do Canal de Sódio Disparado por Voltagem/síntese química , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacocinética , Bloqueadores do Canal de Sódio Disparado por Voltagem/uso terapêuticoRESUMO
Replacement of the piperidine ring in the lead benzenesulfonamide Nav1.7 inhibitor 1 with a weakly basic morpholine core resulted in a significant reduction in Nav1.7 inhibitory activity, but the activity was restored by shortening the linkage from methyleneoxy to oxygen. These efforts led to a series of morpholine-based aryl sulfonamides as isoform-selective Nav1.7 inhibitors. This report describes the synthesis and SAR of these analogs.
Assuntos
Morfolinas/farmacologia , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Sulfonamidas/farmacologia , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Morfolinas/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/síntese química , Bloqueadores do Canal de Sódio Disparado por Voltagem/químicaRESUMO
A series of acidic diaryl ether heterocyclic sulfonamides that are potent and subtype selective NaV1.7 inhibitors is described. Optimization of early lead matter focused on removal of structural alerts, improving metabolic stability and reducing cytochrome P450 inhibition driven drug-drug interaction concerns to deliver the desired balance of preclinical in vitro properties. Concerns over nonmetabolic routes of clearance, variable clearance in preclinical species, and subsequent low confidence human pharmacokinetic predictions led to the decision to conduct a human microdose study to determine clinical pharmacokinetics. The design strategies and results from preclinical PK and clinical human microdose PK data are described leading to the discovery of the first subtype selective NaV1.7 inhibitor clinical candidate PF-05089771 (34) which binds to a site in the voltage sensing domain.
Assuntos
Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Éteres Fenílicos/farmacologia , Sulfonamidas/farmacologia , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Linhagem Celular , Citocromo P-450 CYP2C9/metabolismo , Inibidores do Citocromo P-450 CYP2C9/síntese química , Inibidores do Citocromo P-450 CYP2C9/química , Inibidores do Citocromo P-450 CYP2C9/farmacocinética , Inibidores do Citocromo P-450 CYP2C9/farmacologia , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A/síntese química , Inibidores do Citocromo P-450 CYP3A/química , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Inibidores do Citocromo P-450 CYP3A/farmacologia , Desenho de Fármacos , Humanos , Microssomos Hepáticos/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.7/química , Éteres Fenílicos/síntese química , Éteres Fenílicos/química , Éteres Fenílicos/farmacocinética , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/farmacocinética , Bloqueadores do Canal de Sódio Disparado por Voltagem/síntese química , Bloqueadores do Canal de Sódio Disparado por Voltagem/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacocinéticaRESUMO
hNav1.7 small molecular inhibitors have attracted lots of attention by its unique analgesic effect. Herein, we report the design and synthesis of a novel series of tetrahydropyridine analogs as hNav1.7 inhibitors for analgesia. Detail structural-activity relationship (SAR) studies were undertaken towards improving hNav1.7 activity, in vitro ADME, and in vivo PK profiles. These efforts resulted in the identification of compound (-)-15h, a highly potent and selective hNav1.7 inhibitor with good ADME and PK profiles.
Assuntos
Analgésicos/química , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Piridinas/química , Sulfonamidas/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/química , Analgésicos/síntese química , Analgésicos/farmacocinética , Animais , Sítios de Ligação , Citocromo P-450 CYP2C9/química , Citocromo P-450 CYP2C9/metabolismo , Desenho de Fármacos , Meia-Vida , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Canal de Sódio Disparado por Voltagem NAV1.7/química , Estrutura Terciária de Proteína , Piridinas/síntese química , Piridinas/farmacocinética , Ratos , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/farmacocinética , Bloqueadores do Canal de Sódio Disparado por Voltagem/síntese química , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacocinéticaRESUMO
The steroidal neurotoxin (-)-batrachotoxin functions as a potent agonist of voltage-gated sodium ion channels (NaVs). Here we report concise asymmetric syntheses of the natural (-) and non-natural (+) antipodes of batrachotoxin, as well both enantiomers of a C-20 benzoate-modified derivative. Electrophysiological characterization of these molecules against NaV subtypes establishes the non-natural toxin enantiomer as a reversible antagonist of channel function, markedly different in activity from (-)-batrachotoxin. Protein mutagenesis experiments implicate a shared binding side for the enantiomers in the inner pore cavity of NaV These findings motivate and enable subsequent studies aimed at revealing how small molecules that target the channel inner pore modulate NaV dynamics.
Assuntos
Batraquiotoxinas/síntese química , Batraquiotoxinas/farmacologia , Proteínas Musculares/antagonistas & inibidores , Bloqueadores do Canal de Sódio Disparado por Voltagem/síntese química , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Animais , Sítios de Ligação , Proteínas Musculares/química , Proteínas Musculares/genética , Mutação Puntual , Estrutura Secundária de Proteína , Ratos , Canais de Sódio/química , Canais de Sódio/genética , Bloqueadores do Canal de Sódio Disparado por Voltagem/químicaRESUMO
Palmyrolide A is a neuroprotective macrolide isolated by Gerwick and coworkers in 2010. This natural product is known to suppress neuronal spontaneous calcium ion oscillations through its voltage-gated sodium channel blocking ability which is of significant interest in CNS drug discovery. Herein, we give a detailed account on total synthesis of (+)-palmyrolide A and synthesis of a focused library of macrocycles around the scaffold, followed by their biological evaluation. Use of the chiral pool approach, Zhu's oxidative homologation, access to unnatural cis-palmyrolide A, preparation of 18 new analogues and identification of macrolides with improved sodium channel blocking activity are the important features of the present paper. As a measure of potency as voltage-gated sodium channel blockers, all the synthesized analogues were profiled for their ability to inhibit the veratridine-stimulated Na(+) influx in murine primary neuronal cultures. Four macrocycles were found to be more potent or comparable to that of the natural product (-)-palmyrolide A. The most potent compound from this series 20 was structurally simplified and readily accessible in good quantities for further biological profiling.