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.
Thomas Ullrich  1 ,  Luca Arista  2 ,  Sven Weiler  2 ,  Sylvie Teixeira-Fouchard  2 ,  Valérie Broennimann  2 ,  Nikolaus Stiefl  2 ,  Victoria Head  2 ,  Ina Kramer  2 ,  Sabine Guth  2
Affiliations
  • 1. Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel CH-4002, Switzerland. Electronic address: [email protected].
  • 2. Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel CH-4002, Switzerland.
PMID: 35276359 DOI: 10.1016/j.bmcl.2022.128667
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).
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