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Tachykinin/neurokinin 3 receptor antagonists: In silico ADME/T analysis of novel compounds for menopause hot flashes therapy
Antagonistas del receptor taquiquinina/neuroquinina 3: Análisis in silico ADME/T de nuevos compuestos para la terapia de los sofocos en la menopausia
Antagonistas do receptor de taquicinina/neurocinina 3: análise ADME/T in silico de novos compostos para a terapia de ondas de calor na menopausa
DOI:
https://doi.org/10.15446/rcciquifa.v51n1.102679Palabras clave:
Hot flashes, menopause, tachykinins, NK3 receptor antagonists, ADMET (en)Ondas de calor, menopausa, taquicininas, antagonistas do receptor NK3, ADMET (pt)
Sofocos, menopausia, taquiquininas, antagonistas del receptor NK3, ADMET (es)
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Introduction: Neurokinin-B receptor (NK3R) activation is tightly involved in the onset of vasomotor symptoms during menopause, yet there are still no NK3R antagonistic drugs approved for hot flashes therapy. Determining the pharmacokinetic properties of current drug candidates is crucial for scaffold identification and prediction of feasible outcomes in future clinical trials. Aim: To develop a pharmacokinetic profile of new NK3R blockers with hot flashes reducing activity and by comparing them with trial-suspended NK3R antagonists (Osanetant & Talnetant), it is expected to identify enhanced properties in novel compounds. Methodology: For in silico evaluation, Smiles were retrieved from PubChem and DrugBank, and further analysis was carried out through ADMETlab and SwissADME to calculate compounds drug-likeness and pharmacokinetics. Results: Pavinetant & Fezolinetant and SB-222.200 & SB-218.795 exhibited higher compliance with drug-likeness rules and more suitable physicochemical properties when compared to Osanetant & Talnetant. ADME/T evaluation showed considerable disparities between groups, yet no significant difference was reported. Pharmacokinetic properties varied irregularly among studied compounds. Conclusion: Novel NK3R antagonists exhibit enhanced properties when compared to formerly suspended ones. Fezolinetant is predicted to have more favorable outcomes based on in silico evaluation.
Introducción: la activación del receptor de neuroquinina-B (NK3R) está estrechamente relacionada con la aparición de síntomas vasomotores durante la menopausia, no obstante, a la fecha no se reportan fármacos antagonistas de NK3R aprobados para el manejo de sofocos. La evaluación de las propiedades farmacocinéticas de los compuestos inhibidores de NK3R resulta indispensable para la identificación de potenciales farmacóforos y para la estimación de posibles resultados en ensayos clínicos. Objetivo: determinar las características farmacocinéticas de los nuevos compuestos inhibidores de NK3R con propiedades reductoras de los fogajes asociados a la menopausia, y por medio de un análisis comparativo con los antagonistas de NK3R cuyo ensayo clínico fue suspendido (Osanetant & Talnetant), se espera identificar propiedades superiores en los nuevos compuestos desarrollados. Metodología: se obtuvieron los códigos Smiles a partir de PubChem y DrugBank, posteriormente, el análisis se basó en el cálculo de las propiedades farmacocinéticas y drug-like mediante las plataformas ADMETlab y SwissADME. Resultados: Pavinetant & Fezolinetant y SB-222.200 & SB-218.795 exhiben mejores propiedades fisicoquímicas y cumplen a mayor cabalidad las reglas drug-likeness al compararse con Osanetant & Talnetant. La evaluación ADMET reveló variaciones entre los grupos, pero ninguna fue significativa. Las propiedades farmacocinéticas varían de forma irregular entre los distintos compuestos. Conclusiones: los antagonistas de NK3R recientemente desarrollados exhibieron propiedades superiores frente a los compuestos de ensayos suspendidos. Los resultados del estudio in silico permiten deducir que el Fezolinetant podría tener mejores resultados en futuros ensayos clínicos.
Introdução: a ativação do receptor de neuroquinina-B (NK3R) está intimamente relacionada ao aparecimento de sintomas vasomotores durante a menopausa, entretanto, até o momento não há relatos de drogas antagonistas de NK3R aprovadas para o manejo das ondas de calor. A avaliação das propriedades farmacocinéticas de compostos inibidores de NK3R é essencial para a identificação de potenciais farmacoforos e para a estimativa de possíveis resultados em ensaios clínicos. Objetivo: determinar as características farmacocinéticas dos novos compostos inibidores de NK3R com propriedades redutoras de ondas de calor associadas à menopausa, e através de uma análise comparativa com os antagonistas de NK3R cujo ensaio clínico foi suspenso (Osanetant & Talnetant), espera-se identificar propriedades superiores nos compostos recém-desenvolvidos. Metodologia: os códigos Smiles foram obtidos do PubChem e DrugBank, posteriormente, a análise foi baseada no cálculo das propriedades farmacocinéticas e farmacocinéticas utilizando as plataformas ADMETlab e SwissADME. Resultados: Pavinetant & Fezolinetant e SB-222.200 & SB-218.795 apresentam melhores propriedades físico-químicas e atendem mais plenamente às regras de “drug-likeness” quando comparados ao Osanetant & Talnetant. A avaliação ADMET revelou variações entre os grupos, mas nenhuma foi significativa. As propriedades farmacocinéticas variam irregularmente entre os diferentes compostos. Conclusões: os antagonistas de NK3R recém-desenvolvidos exibiram propriedades superiores em relação aos compostos de teste suspensos. Os resultados do estudo in silico permitem nos deduzir que o Fezolinetant poderá ter melhores resultados em futuros ensaios clínicos.
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