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
  • 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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