Lung-Tailored Pyrrolo-pyrimidine DDR Inhibitors Designed for Optimized Local Delivery
Roberta Mazzucato, Nicoló Iotti, Eleonora Ghidini, Andrea Rizzi, Fabio Rancati, Serena Bertolini, Fabio Bignami, Alessandro Fioni, Valentina Mileo, Fabio Vaccaro, Allisson Freire Bento, Annalisa Murgo, Anna Maria Capelli, Benjamin Paul Whittaker, Charlotte Matthews, Elizabeth Hann, Daniel Todd, Veronica Marinoni, Laura CarzanigaAbstract
Preclinical studies highlighted the key role of Discoidin Domain Receptors (DDRs) in fibrotic processes, making them promising targets for Idiopathic Pulmonary Fibrosis (IPF) treatment. In this work, we describe the design of a novel class of DDR inhibitors and their subsequent optimization toward inhaled delivery. Following a structure-based approach, we identified two chemical series based on 5:6 heterocyclic cores showing nanomolar affinity for DDR1 and DDR2 and a promising kinome selectivity profile. An inhaled-by-design medchem strategy was then applied to optimize potency, phys-chem, and in vitro ADME properties, tailored to achieve lung-restricted compounds. This effort resulted in the discovery of compound 25, a novel and highly potent DDR inhibitor that combined antifibrotic activity in a TGFβ-induced in vitro fibrosis model with an outstanding pharmacokinetic profile and the desired lung-targeted behavior following inhaled administration.