Design, synthesis, and biological evaluation of spiroindolines as novel inducers of oligodendrocyte progenitor cell differentiation-Use of a conformation-based hypothesis to facilitate compound design

Bioorg Med Chem Lett. 2020 Aug 15;30(16):127299. doi: 10.1016/j.bmcl.2020.127299. Epub 2020 Jun 2.

Abstract

Inducing oligodendrocyte progenitor cell (OPC) differentiation is a novel therapeutic strategy for the treatment of demyelinating diseases such as multiple sclerosis (MS). In the preceding article, we detailed the discovery of compound 1, a potent inducer of OPC differentiation possessing a characteristic spiroindoline structure. Also, we found that N-methylation and des-carbonyl compound 1 (4) led to a loss in potency. Herein, we describe our investigations of a conformation-based hypothesis for OPC differentiation activity based on the preferred conformation of the spiro core, and further structure-activity relationship (SAR) exploration led to the identification of 6-CF3 derivative 8, which was more potent compared to compound 1.

Keywords: Conformational analysis; Multiple sclerosis (MS); Myelin; Oligodendrocyte progenitor cell (OPC); Spiroindoline.

MeSH terms

  • Animals
  • Cell Differentiation
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Indoles / chemical synthesis
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Molecular Structure
  • Oligodendrocyte Precursor Cells / drug effects*
  • Rats
  • Spiro Compounds / chemical synthesis
  • Spiro Compounds / chemistry
  • Spiro Compounds / pharmacology*
  • Structure-Activity Relationship

Substances

  • Indoles
  • Spiro Compounds
  • indoline