2. Academic Validation
  3. 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

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

Affiliations

  • 1 Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel CH-4002, Switzerland. Electronic address: thomas.ullrich@novartis.com.
  • 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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