A medicinal-chemistry-guided approach to selective and druglike sigma 1 ligands
| Autor: | Maria Carme Calvet, Leonardo Salgado, Júlia Alegre, Daniel Zamanillo, José Miguel Vela, David Vano, Maria Teresa Serafini, Enric Hernandez, Helmut Buschmann, Rosalia Pascual, Alberto Dordal, Sandra Yeste, Núria Cano, Marisol Escriche, Jordi Corbera, Daniel Martínez, Raquel Pérez, Mónica Carro, Jörg Holenz, Francesc Andreu |
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| Rok vydání: | 2006 |
| Předmět: |
Magnetic Resonance Spectroscopy
Stereochemistry hERG Ligands Biochemistry Mass Spectrometry Structure-Activity Relationship Drug Discovery Structure–activity relationship Animals Humans Receptors sigma General Pharmacology Toxicology and Pharmaceutics Receptor ADME Pharmacology biology CYP3A4 Chemistry Organic Chemistry CYP1A2 Cytochrome P450 Rats biology.protein Microsomes Liver Molecular Medicine Caco-2 Cells Selectivity Protein Binding |
| Zdroj: | ChemMedChem. 1(1) |
| ISSN: | 1860-7179 |
| Popis: | Based on a medicinal-chemistry-guided approach, three novel series of druglike cycloalkyl-annelated pyrazoles were synthesized and display high affinity (pKi>8) for the sigma1 receptor. Structure-affinity relationships were established, and the different scaffolds were optimized with respect to sigma1 binding and selectivity versus the sigma2 receptor and the hERG channel, resulting in selective compounds that have Ki values (for sigma1) in the subnanomolar range. Selected compounds were screened for cytochrome P450 inhibition (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4), metabolic stability (rat and human liver microsomes), and cell-membrane permeability (Caco-2). They showed favorable in vitro ADME properties as well as favorable calculated druglike and experimental physicochemical properties. Furthermore, compounds 7 f and 17 a, for example, displayed high selectivity (affinity) for the sigma1 receptor against a wide range of other receptors (>60). With these valuable tool compounds in hand, we are further exploring the role of the sigma1 receptor in relevant animal models corresponding to such medicinal indications as drug abuse, pain, depression, anxiety, and psychosis. |
| Databáze: | OpenAIRE |
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