Tricyclic pyrazoles part 7. Discovery of potent and selective dihydrothienocyclopentapyrazole derived CB2 ligands

Eur J Med Chem. 2014 Oct 6;85:747-57. doi: 10.1016/j.ejmech.2014.08.042. Epub 2014 Aug 13.

Abstract

A series of dihydrothienocyclopentapyrazole-based derivatives was synthesized and evaluated for the affinity at CB1 and CB2 receptors. The major term, the 6-methyl-1-(1,4-dichlorophenyl)-N-piperidinyl)-1,4-dihydrothieno[2',3'-4,5]cyclopenta[1,2-c]pyrazole-3-carboxamide (6a), displayed a high affinity and good selectivity for CB2 receptors (Ki values of 2.30 nM for CB2 receptor and 440 nM for CB1 receptors respectively). Subsequent analogue preparation resulted in the identification of compounds such as 6b, 6d, 6e, 6k, 6l, 6m, 6s and 6t that showed 1.3-485 fold selectivity for CB2 receptors with potencies in the 1.1-7.2 nM range. These compounds profiled as full agonists at CB2 receptor in an inhibition assay of P-ERK 1/2 up regulation in HL-60 cells.

Keywords: Amides; CB2 agonists; Cannabinoid receptors; Dihydrothienocyclopentapyrazole; Thiophene tricycles.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Drug Design*
  • HL-60 Cells
  • Humans
  • Ligands
  • Protein Binding
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry*
  • Pyrazoles / metabolism*
  • Receptor, Cannabinoid, CB2 / metabolism*
  • Substrate Specificity

Substances

  • Ligands
  • Pyrazoles
  • Receptor, Cannabinoid, CB2
  • pyrazole