Design, Synthesis, and Activity of a Novel Series of Pyridazine-Based ALK5 Inhibitors

  • ACS Med Chem Lett. 2024 Oct 23;15(11):1925-1932. doi: 10.1021/acsmedchemlett.4c00374.
Daniele Pala  1 ,  Paolo Ronchi  1 ,  Donatella Rescigno  2 ,  Barbara Bertani  2 ,  Anna Maria Capelli  1 ,  Sara Guariento  1 ,  Gessica Marchini  1 ,  Marco Milioli  1 ,  Nicola Cesari  1 ,  Giuseppina Federico  1 ,  Andrea Grandi  1 ,  Franco F Stellari  1 ,  Sergio Xanxo Fernandez  1 ,  Alice Pappani  1 ,  Luca Venturi  1 ,  Matteo Biagetti  1 ,  Maurizio Civelli  1 ,  Teresa Semeraro  2 ,  Federica Bianchi  2 ,  Iuni M L Trist  2 ,  Rosaria Remelli  2 ,  Elisabetta Armani  1 ,  Daniela Pizzirani  1
Affiliations
  • 1. Chiesi Farmaceutici S.p.A., Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy.
  • 2. Aptuit, an Evotec Company, Via Alessandro Fleming 4, 37135 Verona, Italy.
PMID: 39563792 DOI: 10.1021/acsmedchemlett.4c00374
Abstract

ALK5 inhibitors represent an attractive therapeutic approach for the treatment of a variety of pathologies, including Cancer and fibrosis. Herein, we report the design and in vitro characterization of a novel series of ALK5 modulators featuring a 4,6-disubstituted pyridazine core. A knowledge-based scaffold-hopping exploration was initially conducted on a restricted set of heteroaromatic cores using available ligand- and structure-based information. The most potent structurally novel hit compound 2A was subsequently subjected to a preliminary optimization for the inhaled delivery, applying physicochemical criteria aimed at minimizing systemic exposure to limit the risk of adverse side effects. The resulting inhibitors showed a marked boost in potency against ALK5 and in vitro ADME properties, potentially favoring lung retention. The optimized hits 20 and 23 might thus be considered promising starting points for the development of novel inhaled ALK5 inhibitors.

Products