Discovery of a novel 2-aminopyrazine-3-carboxamide as a potent and selective inhibitor of Activin Receptor-Like Kinase-2 (ALK2) for the treatment of fibrodysplasia ossificans progressiva

Bioorg Med Chem Lett. 2022 May 15:64:128667. doi: 10.1016/j.bmcl.2022.128667. Epub 2022 Mar 8.

Abstract

Inhibition of mutant activin A type-1 receptor ACVR1 (ALK2) signaling by small-molecule drugs is a promising therapeutic approach to treat fibrodysplasia ossificans progressiva (FOP), an ultra-rare disease leading to progressive soft tissue heterotopic ossification with no curative treatment available to date. Here, we describe the synthesis and in vitro characterization of a novel series of 2-aminopyrazine-3-carboxamides that led to the discovery of Compound 23 showing excellent biochemical and cellular potency, selectivity over other BMP and TGFβ signaling receptor kinases, and a favorable in vitro ADME profile.

Keywords: Activin receptor-like kinase-2 (ALK2); Aminopyrazines; Bone morphogenetic protein (BMP) signaling; Fibrodysplasia ossificans progressiva (FOP).

MeSH terms

  • Activin Receptors, Type I
  • Humans
  • Myositis Ossificans* / drug therapy
  • Ossification, Heterotopic*
  • Pyrazines / pharmacology
  • Pyrazines / therapeutic use
  • Signal Transduction

Substances

  • Pyrazines
  • 2-aminopyrazine
  • Activin Receptors, Type I