Thiazole‐Based σ1 Receptor Ligands: Diversity by Late‐Stage C−H Arylation of Thiazoles, Structure–Affinity and Selectivity Relationships, and Molecular Interactions

Spirocyclic thiophene derivatives represent promising σ1 ligands with high σ1 affinity and selectivity over the σ2 subtype. To increase ligand efficiency, the thiophene ring was replaced bioisosterically by a thiazole ring, and the pyran ring was opened. Late‐stage diversification by regioselective...

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Veröffentlicht in:ChemMedChem 2017-07, Vol.12 (13), p.1070-1080
Hauptverfasser: Kokornaczyk, Artur K., Schepmann, Dirk, Yamaguchi, Junichiro, Itami, Kenichiro, Laurini, Erik, Fermeglia, Maurizio, Pricl, Sabrina, Wünsch, Bernhard
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Sprache:eng
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Zusammenfassung:Spirocyclic thiophene derivatives represent promising σ1 ligands with high σ1 affinity and selectivity over the σ2 subtype. To increase ligand efficiency, the thiophene ring was replaced bioisosterically by a thiazole ring, and the pyran ring was opened. Late‐stage diversification by regioselective C−H arylation of thiazoles 9 a–c resulted in a set of 53 compounds with high diversity. This set of compounds was analyzed with respect to σ1 affinity, σ1/σ2 selectivity, lipophilicity (logD7.4), lipophilicity‐corrected ligand efficiency (LELP), and molecular target interactions. The most promising candidates were pyridyl‐substituted thiazole derivatives 33 c (2‐(1‐benzyl‐4‐ethoxypiperidin‐4‐yl)‐5‐(pyridin‐3‐yl)thiazole) and 34 c (2‐(1‐benzyl‐4‐ethoxypiperidin‐4‐yl)‐5‐(pyridin‐4‐yl)thiazole), possessing low‐nanomolar σ1 affinity (Ki=1.3 and 1.9 nm), high σ1/σ2 selectivity (>1500‐fold), low lipophilicity (logD7.4=1.8) and very good ligand efficiency (LELP=5.5), indicating promising pharmacodynamics and pharmacokinetics. Molecular simulation studies, including docking and deconvolution of the free binding energy into its major components, led to decreased hydrophobic stabilization of pyridyl derivatives 33 c and 34 c, which was compensated by lower desolvation energy. Bioisosteric benefits: To increase σ1 receptor ligand efficiency of spirocylic thiophenes, the thiophene ring was replaced with a thiazole, and the pyran ring was opened to afford 53 derivatives. Among these, two pyridyl‐substituted thiazole derivatives were most promising, with low‐nanomolar σ1 affinity, high σ1/σ2 selectivity, low lipophilicity, and very good ligand efficiency, indicating promising pharmacodynamics and pharmacokinetics.
ISSN:1860-7179
1860-7187
DOI:10.1002/cmdc.201700166