Asymmetric Hydroboration Approach to the Scalable Synthesis of ((1R,3S)-1-Amino-3-((R)-6-hexyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopentyl)methanol (BMS-986104) as a Potent S1P1 Receptor Modulator

J Med Chem. 2016 Dec 22;59(24):11138-11147. doi: 10.1021/acs.jmedchem.6b01433. Epub 2016 Dec 7.

Abstract

We describe a highly efficient route for the synthesis of 4a (BMS-986104). A key step in the synthesis is the asymmetric hydroboration of trisubstituted alkene 6. Particularly given the known difficulties involved in this type of transformation (6 → 7), the current methodology provides an efficient approach to prepare this class of compounds. In addition, we disclose the efficacy of 4a in a mouse EAE model, which is comparable to 4c (FTY720). Mechanistically, 4a exhibited excellent remyelinating effects on lysophosphatidylcholine (LPC) induced demyelination in a three-dimensional brain cell culture assay.

MeSH terms

  • Animals
  • Cells, Cultured
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Encephalomyelitis, Autoimmune, Experimental / drug therapy*
  • Female
  • HEK293 Cells
  • Humans
  • Lymphocytes / drug effects
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Molecular Structure
  • Naphthalenes / chemical synthesis
  • Naphthalenes / chemistry
  • Naphthalenes / pharmacology*
  • Receptors, Lysosphingolipid / agonists*
  • Structure-Activity Relationship

Substances

  • 1-amino-3-((R)-6-hexyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopentyl)methanol
  • Naphthalenes
  • Receptors, Lysosphingolipid