Fibroblast growth factor receptor modulators employing diamines with reduced phospholipidosis-inducing potential

Bioorg Med Chem. 2020 Jul 15;28(14):115562. doi: 10.1016/j.bmc.2020.115562. Epub 2020 May 24.

Abstract

SUN13837 (1), a fibroblast growth factor receptor modulator, has been an attractive candidate for treating neurodegenerative diseases. However, one of its metabolites, N-benzyl-4-(methylamino)piperidine (BMP), turned out to possess phospholipidosis-inducing potential (PLIP) in vitro. To obtain SUN13837 analogs with reduced phospholipidosis risk, we replaced BMP with other diamines possessing low PLIP. Our effort led to the discovery of compound 6 with increased efficacy. Further structural modifications to reduce hydrogen bond donors afforded 17 with improved brain exposure. Oral administration of 17 at 1 mg/kg once daily for 10 days showed enhanced recovery of coordinated movement in a rat acute stroke model, suggesting that it is a promising follow-up compound for 1 with reduced risk of phospholipidosis.

Keywords: Brain Kp; FGFR modulator; P-gp; PAMPA; Phospholipidosis.

MeSH terms

  • Animals
  • Caco-2 Cells
  • Diamines / chemical synthesis
  • Diamines / chemistry
  • Diamines / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • Male
  • Microsomes, Liver / chemistry
  • Microsomes, Liver / metabolism
  • Molecular Structure
  • Neurons / drug effects
  • Neurons / metabolism
  • Neuroprotective Agents / chemical synthesis
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacology*
  • Phospholipids / antagonists & inhibitors*
  • Phospholipids / metabolism
  • Rats
  • Rats, Wistar
  • Receptors, Fibroblast Growth Factor / metabolism*
  • Structure-Activity Relationship

Substances

  • Diamines
  • Neuroprotective Agents
  • Phospholipids
  • Receptors, Fibroblast Growth Factor