RESUMO
NBI-921352 (formerly XEN901) is a novel sodium channel inhibitor designed to specifically target NaV1.6 channels. Such a molecule provides a precision-medicine approach to target SCN8A-related epilepsy syndromes (SCN8A-RES), where gain-of-function (GoF) mutations lead to excess NaV1.6 sodium current, or other indications where NaV1.6 mediated hyper-excitability contributes to disease (Gardella and Møller, 2019; Johannesen et al., 2019; Veeramah et al., 2012). NBI-921352 is a potent inhibitor of NaV1.6 (IC500.051 µM), with exquisite selectivity over other sodium channel isoforms (selectivity ratios of 756 X for NaV1.1, 134 X for NaV1.2, 276 X for NaV1.7, and >583 Xfor NaV1.3, NaV1.4, and NaV1.5). NBI-921352is a state-dependent inhibitor, preferentially inhibiting inactivatedchannels. The state dependence leads to potent stabilization of inactivation, inhibiting NaV1.6 currents, including resurgent and persistent NaV1.6 currents, while sparing the closed/rested channels. The isoform-selective profile of NBI-921352 led to a robust inhibition of action-potential firing in glutamatergic excitatory pyramidal neurons, while sparing fast-spiking inhibitory interneurons, where NaV1.1 predominates. Oral administration of NBI-921352 prevented electrically induced seizures in a Scn8a GoF mouse,as well as in wild-type mouse and ratseizure models. NBI-921352 was effective in preventing seizures at lower brain and plasma concentrations than commonly prescribed sodium channel inhibitor anti-seizure medicines (ASMs) carbamazepine, phenytoin, and lacosamide. NBI-921352 waswell tolerated at higher multiples of the effective plasma and brain concentrations than those ASMs. NBI-921352 is entering phase II proof-of-concept trials for the treatment of SCN8A-developmental epileptic encephalopathy (SCN8A-DEE) and adult focal-onset seizures.
Assuntos
Epilepsia , Canal de Sódio Disparado por Voltagem NAV1.6 , Animais , Mutação com Ganho de Função , Camundongos , Mutação , Canal de Sódio Disparado por Voltagem NAV1.6/genética , Neurônios/fisiologia , Ratos , Sódio , Bloqueadores dos Canais de Sódio/farmacologiaRESUMO
We report on a novel series of aryl sulfonamides that act as nanomolar potent, isoform-selective inhibitors of the human sodium channel hNaV1.7. The optimization of these inhibitors is described. We aimed to improve potency against hNaV1.7 while minimizing off-target safety concerns and generated compound 3. This agent displayed significant analgesic effects in rodent models of acute and inflammatory pain and demonstrated that binding to the voltage sensor domain 4 site of NaV1.7 leads to an analgesic effect in vivo. Our findings corroborate the importance of hNaV1.7 as a drug target for the treatment of pain.
RESUMO
The redesign of the previously reported thiophene-3-yl-methyl urea series, as a result of potential cardiotoxicity, was successfully accomplished, resulting in the identification of a novel potent series of CCR5 antagonists containing the imidazolidinylpiperidinyl scaffold. The main redesign criteria were to reduce the number of rotatable bonds and to maintain an acceptable lipophilicity to mitigate hERG inhibition. The structure-activity relationship (SAR) that was developed was used to identify compounds with the best pharmacological profile to inhibit HIV-1. As a result, five advanced compounds, 6d, 6e, 6i, 6h, and 6k, were further evaluated for receptor selectivity, antiviral activity against CCR5 using (R5) HIV-1 clinical isolates, and in vitro and in vivo safety. On the basis of these results, 6d and 6h were selected for further development.
Assuntos
Fármacos Anti-HIV/farmacologia , Benzoatos/farmacologia , Antagonistas dos Receptores CCR5 , Replicação Viral/efeitos dos fármacos , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Benzoatos/síntese química , Benzoatos/química , Células CHO , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cricetinae , Cricetulus , Desenho de Fármacos , Células HEK293 , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Imidazóis/síntese química , Imidazóis/química , Imidazóis/farmacologia , Imidazolidinas/química , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/virologia , Modelos Químicos , Estrutura Molecular , Piperidinas/química , Receptores CCR5/genética , Receptores CCR5/metabolismo , Relação Estrutura-AtividadeRESUMO
Based on the attrition rate of CCR5 small molecule antagonists in the clinic the discovery and development of next generation antagonists with an improved pharmacology and safety profile is necessary. Herein, we describe a combined molecular modeling, CCR5-mediated cell fusion, and receptor site-directed mutagenesis approach to study the molecular interactions of six structurally diverse compounds (aplaviroc, maraviroc, vicriviroc, TAK-779, SCH-C and a benzyloxycarbonyl-aminopiperidin-1-yl-butane derivative) with CCR5, a coreceptor for CCR5-tropic HIV-1 strains. This is the first study using an antifusogenic assay, a model of the interaction of the gp120 envelope protein with CCR5. This assay avoids the use of radioactivity and HIV infection assays, and can be used in a high throughput mode. The assay was validated by comparison with other established CCR5 assays. Given the hydrophobic nature of the binding pocket several binding models are suggested which could prove useful in the rational drug design of new lead compounds.
Assuntos
Antagonistas dos Receptores CCR5 , Inibidores da Fusão de HIV/farmacologia , HIV-1/fisiologia , HIV-1/efeitos dos fármacos , Ensaios de Triagem em Larga Escala , Modelos Moleculares , Mutagênese Sítio-Dirigida , Mutação , Conformação Proteica , Receptores CCR5/genética , Reprodutibilidade dos Testes , Estereoisomerismo , Internalização do VírusRESUMO
A novel series of CCR5 antagonists were identified based on the redesign of Schering C. An SAR was established based on inhibition of CCR5 (RANTES) binding and these compounds exhibited potent inhibition of R5 HIV-1 replication in peripheral blood mononuclear cells.
Assuntos
Amidas/química , Antagonistas dos Receptores CCR5 , Óxidos N-Cíclicos/química , HIV-1/efeitos dos fármacos , Piperidinas/química , Piridinas/química , Amidas/síntese química , Amidas/farmacocinética , Animais , Cães , Desenho de Fármacos , Humanos , Oximas , Ratos , Receptores CCR5/metabolismo , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacosRESUMO
An early lead from the AMD070 program was optimized and a structure-activity relationship was developed for a novel series of heterocyclic containing compounds. Potent CXCR4 antagonists were identified based on anti-HIV-1 activity and Ca(2+) flux inhibition that displayed good pharmacokinetics in rat and dog.
Assuntos
Fármacos Anti-HIV/síntese química , HIV-1/efeitos dos fármacos , Receptores CXCR4/antagonistas & inibidores , Replicação Viral/efeitos dos fármacos , Administração Oral , Aminoquinolinas , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacocinética , Benzimidazóis , Butilaminas , Sinalização do Cálcio , Cães , HIV-1/fisiologia , Compostos Heterocíclicos com 1 Anel/química , Humanos , Ratos , Receptores CXCR4/metabolismo , Relação Estrutura-AtividadeRESUMO
Bis-tetraazamacrocycles such as the bicyclam AMD3100 (1) are a class of potent and selective anti-HIV-1 agents that inhibit virus replication by binding to the chemokine receptor CXCR4, the coreceptor for entry of X4 viruses. By sequential replacement and/or deletion of the amino groups within the azamacrocyclic ring systems, we have determined the minimum structural features required for potent antiviral activity in this class of compounds. All eight amino groups are not required for activity, the critical amino groups on a per ring basis are nonidentical, and the overall charge at physiological pH can be reduced without compromising potency. This approach led to the identification of several single ring azamacrocyclic analogues such as AMD3465 (3d), 36, and 40, which exhibit EC(50)'s against the cytopathic effects of HIV-1 of 9.0, 1.0, and 4.0 nM, respectively, antiviral potencies that are comparable to 1 (EC(50) against HIV-1 of 4.0 nM). More importantly, however, the key structural elements of 1 required for antiviral activity may facilitate the design of nonmacrocyclic CXCR4 antagonists suitable for HIV treatment via oral administration.