Tricyclic Triazoles as σ1 Receptor Antagonists for Treating Pain
| Autor: | Carmen Almansa, Inés Álvarez, M. Ángeles Sarmentero, José M López-Valbuena, Alba Vidal-Torres, J.L. Diaz, Ana I. Oliva, Raquel Enrech, Daniel Font, Pilar Pérez, Félix Cuevas, Enrique J. Cobos, José Miguel Vela, Cruz Miguel Cendán, Ana Montero, Miquel A. Pericàs, Paula Álvarez-Bercedo, Sandra Yeste |
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| Rok vydání: | 2021 |
| Předmět: |
chemistry.chemical_classification
0303 health sciences Stereochemistry Analgesic Biological activity Absorption (skin) Metabolism 01 natural sciences In vitro 0104 chemical sciences 010404 medicinal & biomolecular chemistry 03 medical and health sciences chemistry Drug Discovery Molecular Medicine Distribution (pharmacology) Receptor 030304 developmental biology Tricyclic |
| Zdroj: | Journal of Medicinal Chemistry. 64:5157-5170 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | The synthesis and pharmacological activity of a new series of 5a,7,8,8a-tetrahydro-4H,6H-pyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine derivatives as potent sigma-1 receptor (σ1R) ligands are reported. A lead optimization program aimed at improving the aqueous solubility of parent racemic nonpolar derivatives led to the identification of several σ1R antagonists with a good absorption, distribution, metabolism, and excretion in vitro profile, no off-target affinities, and characterized by a low basic pKa (around 5) that correlates with high exposure levels in rodents. Two compounds displaying a differential brain-to-plasma ratio distribution profile, 12lR and 12qS, exhibited a good analgesic profile and were selected as preclinical candidates for the treatment of pain. |
| Databáze: | OpenAIRE |
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