2. Academic Validation
  3. Discovery of a Novel Lung-Restricted ALK5 Inhibitor for the Treatment of Idiopathic Pulmonary Fibrosis

Discovery of a Novel Lung-Restricted ALK5 Inhibitor for the Treatment of Idiopathic Pulmonary Fibrosis

  • J Med Chem. 2026 Jun 11;69(11):13002-13027. doi: 10.1021/acs.jmedchem.5c03825.
Paolo Ronchi 1,  Daniela Pizzirani 1,  Daniele Pala 1,  Anna Maria Capelli 1,  Donatella Rescigno 2,  Barbara Bertani 2,  Iuni M L Trist 2,  Marco Milioli 1,  Nicola Cesari 1,  Giuseppina Federico 1,  Alice Pappani 1,  Luca Venturi 1,  Daniel Pecorari 1,  Sara Guariento 1,  Gessica Marchini 1,  Franco F Stellari 1,  Sergio Xanxo Fernandez 1,  Matteo Biagetti 1,  Maurizio Civelli 1,  Federica Bianchi 2,  Rosaria Remelli 2,  Alessio Barilli 2,  Daniela Pompilio 2,  Alison J Hole 3,  Sofia Caria 3,  Elisabetta Armani 1
Affiliations

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.
  • 3 Evotec (U.K.) Limited, 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, U.K.
PMID: 42152170 DOI: 10.1021/acs.jmedchem.5c03825
Abstract

As part of a therapeutic approach to idiopathic pulmonary fibrosis (IPF) using inhaled ALK5 inhibitors, which enable targeted lung delivery while minimizing systemic side effects, this work describes the optimization process of a previously reported series featuring a 4,6-disubstituted pyridazine core. The medicinal chemistry exploration, aimed at increasing cellular potency while keeping physicochemical and ADME properties favorable for inhalation, was directed to the functionalization of the 3-position in the pyridazine core. An efficient SAR exploration, supported by a late-stage functionalization (LSF) approach, led to the identification of a small set of compounds worthy of in vivo characterization. Compound 20 showed a persistent and lung-restricted target engagement in a pharmacodynamic model, which well-correlated with its in vitro solubility measured in simulated lung fluid (SLF). When tested in a mouse model of lung fibrosis, 20 showed remarkable efficacy, thus representing an advanced lead candidate for the development of topical antifibrotic therapeutics.

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