Inhaled-by-design pyrrolopyrimidine DDR1/2 inhibitors target pulmonary fibrosis
- Structure-based design delivered two 5:6 heterocyclic series with strong DDR1/DDR2 affinity and a promising kinome selectivity profile.
- An inhaled-by-design strategy then tuned potency, physicochemical and in vitro ADME properties toward lung-restricted compounds.
- Compound 25 combined antifibrotic activity in a TGF-β-induced in vitro fibrosis model with a favorable pharmacokinetic profile for local delivery.
💡 Points
Inhaled kinase inhibitors live or die on lung retention versus systemic clearance, and designing for that from the start is the right call rather than retrofitting a systemic compound. The pitfalls I'd watch are lysosomal trapping and mucociliary clearance, which in vitro ADME rarely captures. DDR biology is compelling in fibrosis, but it's still a target waiting for clinical validation.
Lung-Tailored Pyrrolo-pyrimidine DDR Inhibitors Designed for Optimized Local Delivery ↗