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.

Thomas Ullrich, Luca Arista, Sven Weiler, Sylvie Teixeira-Fouchard, Valérie Broennimann, Nikolaus Stiefl, Victoria Head, Ina Kramer, Sabine Guth

Bioorganic & medicinal chemistry letters 2022 May 15

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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. Copyright © 2022 Elsevier Ltd. All rights reserved.

Citation

Thomas Ullrich, Luca Arista, Sven Weiler, Sylvie Teixeira-Fouchard, Valérie Broennimann, Nikolaus Stiefl, Victoria Head, Ina Kramer, Sabine Guth. 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. Bioorganic & medicinal chemistry letters. 2022 May 15;64:128667