2. Academic Validation
  3. A Journey through Scaffolds: Indolines, Pyrrolidines, and Azetidines in the Quest for Inhaled DDR Inhibitors for IPF

A Journey through Scaffolds: Indolines, Pyrrolidines, and Azetidines in the Quest for Inhaled DDR Inhibitors for IPF

  • J Med Chem. 2026 Feb 20. doi: 10.1021/acs.jmedchem.5c02830.
Laura Carzaniga 1,  Fabio Rancati 1,  Andrea Rizzi 1,  Roberta Mazzucato 1,  Nicoló Iotti 1,  Eleonora Ghidini 1,  Serena Bertolini 1,  Fabio Bignami 1,  Alessandro Fioni 1,  Valentina Mileo 1,  Fabio Vaccaro 1,  Annalisa Murgo 1,  Allisson Freire Bento 1,  Anna Maria Capelli 1,  Benjamin Paul Whittaker 2,  Stefano Levanto 2,  Robert S L Chapman 2,  Zuzana Hamasova 2,  Charlotte J Hardy 2,  David Edward Clark 2,  Ruth Allen 2,  Mike A Briggs 2,  Elizabeth Hann 2,  Shannon Lee 2,  Charlotte Matthews 2,  Daniel Todd 2,  Julie Hawkins 2,  Marta Giuliani 1
Affiliations

Affiliations

  • 1 Chiesi Farmaceutici S.p.A., Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy.
  • 2 Charles River Laboratories, Chesterford Research Park, Saffron Walden CB10 1XL, U.K.
PMID: 41715301 DOI: 10.1021/acs.jmedchem.5c02830
Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease, with excessive Extracellular Matrix (ECM) deposition impairing gas exchange, leading to lung failure. Current treatments are limited, with lung transplantation as the only cure. Discoidin Domain Receptors (DDR1/2), collagen-activated Receptor Tyrosine Kinases, orchestrate Collagen deposition in fibrotic diseases. We report the discovery and optimization of novel DDR1/2 kinase-domain inhibitors suitable for inhaled administration. Starting from a benzylamine scaffold, three chemical series, namely indolines, pyrrolidines, and azetidines, were explored. The first two showed potent DDR1 inhibition and lung retention but faced safety and selectivity challenges. The azetidine compound 37 was identified as the most promising one for its nanomolar potency, improved kinase selectivity, reduced cardiotoxicity risk, and excellent inhaled PK profile. It demonstrated activity in a collagen-induced pharmacodynamic mouse model, supporting its potential as an inhaled DDR inhibitor for IPF and validating the azetidine scaffold as a promising starting point for further optimization.

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