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

Artur K. Kokornaczyk, Dirk Schepmann, Junichiro Yamaguchi, Kenichiro Itami, Erik Laurini, Maurizio Fermeglia, Sabrina Pricl, Bernhard Wünsch*

*この研究の対応する著者

研究成果: Article査読

5 被引用数 (Scopus)

抄録

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, σ12 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 σ12 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.

本文言語English
ページ(範囲)1070-1080
ページ数11
ジャーナルChemMedChem
12
13
DOI
出版ステータスPublished - 2017 7月 6

ASJC Scopus subject areas

  • 生化学
  • 分子医療
  • 薬理学
  • 創薬
  • 薬理学、毒性学および薬学(全般)
  • 有機化学

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