Discovery of 3-(4-sulfamoylnaphthyl)pyrazolo[1,5-a]pyrimidines as potent and selective ALK2 inhibitors

Bioorg Med Chem Lett. 2018 Nov 1;28(20):3356-3362. doi: 10.1016/j.bmcl.2018.09.006. Epub 2018 Sep 6.

Abstract

The pyrazolo[1,5-a]pyrimidine LDN-193189 is a potent inhibitor of activin receptor-like kinase 2 (ALK2) but is nonselective for highly homologous ALK3 and shows only modest kinome selectivity. Herein, we describe the discovery of a novel series of potent and selective ALK2 inhibitors by replacing the quinolinyl with a 4-(sulfamoyl)naphthyl, yielding ALK2 inhibitors that exhibit not only excellent discrimination versus ALK3 but also high kinome selectivity. In addition, the optimized compound 23 demonstrates good ADME and in vivo pharmacokinetic properties.

Keywords: ALK2; FOP; LDN-193189; Pyrazolo[1,5-a]pyrimidine; Sulfamoylnaphthyl.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activin Receptors, Type I / antagonists & inhibitors*
  • Activin Receptors, Type I / chemistry
  • Animals
  • Binding Sites
  • Drug Discovery
  • Humans
  • Mice, Inbred C57BL
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacokinetics
  • Pyrazoles / pharmacology*
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacokinetics
  • Pyrimidines / pharmacology*
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacokinetics
  • Sulfonamides / pharmacology*

Substances

  • LDN 193189
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyrimidines
  • Sulfonamides
  • ACVR1 protein, human
  • Activin Receptors, Type I
  • Acvr1 protein, mouse