Jordi Bach, Daniel Pérez, Cristina Esteve, Oriol Llera, Lorena Taboada, Paul R Eastwood, Jacob González, Lluís Pagès, Blanca López, Rosario Ramón, Laura Grau, Alberto Ortega, Alfredo González, Francesc Biosca, Jordi Serrat, Stephen Connolly, Silvia Fonquerna, Paul Beswick, Jordi Gràcia, Estrella Lozoya, Josep M Huerta, Sonia Espinosa, Adelina Orellana, Mónica Maldonado, Juan Perez-Andres, Carlos Rodergas Mir, Elena Calaf, Joan Albertí, Mariona Aulí, Cristina Carreño, Elena Calama, Jorge De Alba, Montserrat Miralpeix, Marta Calbet, Isabel Ramis
Relevant cytokines involved in inflammatory processes in asthma and Chronic Obstructive Pulmonary Disease (COPD) signal through the Janus kinase (JAK) proteins. Therefore, a JAK inhibitor blocking multiple cytokine signaling pathways constitutes a potential new anti-inflammatory therapy for these diseases. Herein is described the discovery and progression of a novel series of pyrazolo[1,5-a]pyridine JAK inhibitors with a profile suitable for inhaled administration. Structural biology-guided design was used to improve potency, kinase selectivity, and lung retention of initial compounds, leading to the identification of compound 18 (LAS194046), a potent and selective pan-JAK inhibitor with an excellent profile for inhaled administration and proven efficacy in the ovalbumin (OVA)-induced airway inflammation model in rat by the inhaled route. As part of the optimization process leading to 18, the relevance of several physicochemical properties in lung retention has also been analyzed.