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

    Research output: Contribution to journalArticle

    3 Citations (Scopus)

    Abstract

    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.

    Original languageEnglish
    Pages (from-to)1070-1080
    Number of pages11
    JournalChemMedChem
    Volume12
    Issue number13
    DOIs
    Publication statusPublished - 2017

    Fingerprint

    Thiazoles
    Molecular interactions
    Ligands
    Thiophenes
    Derivatives
    Pharmacodynamics
    Pyrans
    Pharmacokinetics
    Deconvolution
    Binding energy
    Stabilization

    Keywords

    • C−H arylation
    • molecular dynamics
    • structure–affinity relationships
    • thiazoles
    • σ receptors

    ASJC Scopus subject areas

    • Molecular Medicine
    • Pharmacology, Toxicology and Pharmaceutics(all)
    • Organic Chemistry

    Cite this

    Thiazole-Based σ1 Receptor Ligands : Diversity by Late-Stage C−H Arylation of Thiazoles, Structure–Affinity and Selectivity Relationships, and Molecular Interactions. / Kokornaczyk, Artur K.; Schepmann, Dirk; Yamaguchi, Junichiro; Itami, Kenichiro; Laurini, Erik; Fermeglia, Maurizio; Pricl, Sabrina; Wünsch, Bernhard.

    In: ChemMedChem, Vol. 12, No. 13, 2017, p. 1070-1080.

    Research output: Contribution to journalArticle

    Kokornaczyk, Artur K. ; Schepmann, Dirk ; Yamaguchi, Junichiro ; Itami, Kenichiro ; Laurini, Erik ; Fermeglia, Maurizio ; Pricl, Sabrina ; Wünsch, Bernhard. / Thiazole-Based σ1 Receptor Ligands : Diversity by Late-Stage C−H Arylation of Thiazoles, Structure–Affinity and Selectivity Relationships, and Molecular Interactions. In: ChemMedChem. 2017 ; Vol. 12, No. 13. pp. 1070-1080.
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    abstract = "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.",
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    AU - Schepmann, Dirk

    AU - Yamaguchi, Junichiro

    AU - Itami, Kenichiro

    AU - Laurini, Erik

    AU - Fermeglia, Maurizio

    AU - Pricl, Sabrina

    AU - Wünsch, Bernhard

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    AB - 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.

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