Tachykinin/neurokinin 3 receptor antagonists: In silico ADME/T analysis of novel compounds for menopause hot flashes therapy

• Autores: Jorge Andrés Barrero, Angélica María González-Clavijo
• Localización: Revista Colombiana de Ciencias Químico-Farmacéuticas, ISSN-e 1909-6356, ISSN 0034-7418, Vol. 51, Nº. 1, 2022, págs. 100-122
• Idioma: inglés
• Títulos paralelos:
  • Antagonistas do receptor de taquicinina/neurocinina 3: análise ADME/T in silico de novos compostos para a terapia de ondas de calor na menopausa
  • Antagonistas del receptor taquiquinina/neuroquinina 3: Análisis in silico ADME/T de nuevos compuestos para la terapia de los sofocos en la menopausia
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• Resumen

  • 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.