JAK (Janus) kinases are a family of four enzymes (JAK1, JAK2, JAK3 and TYK2) implicated in cell signalling processes relevant in immunity and inflammation. In recent years, many efforts have been devoted to the development of JAK inhibitors for the treatment of myeloproliferative and autoimmune diseases which have culminated in the progression of several compounds into clinical trials. Among them, Ruxolitinib, Tofacitinib and Baricitinib have reached the market for the oral treatment of myelofibrosis and rheumatoid arthritis. On the other hand, the potential use of JAK inhibitors for the treatment of inflammatory respiratory diseases has been far less explored with no compounds in clinical development. This presentation will focus on the design, synthesis and biological activity of a series of novel pyrazolo[1,5-a]pyridines and imidazo[1,2-a]pyridines as potent pan-JAK inhibitors with a suitable profile for inhaled administration. Work in this series culminated in the identification of LAS194046 as preclinical candidate. A rationally designed modification of a competitor’s JAK3 inhibitor resulted in the discovery of a novel series of pan-JAK inhibitors bearing pyrazolo[1,5-a]pyridine and imidazo[1,2-a]pyridine scaffolds as hinge binder motifs. Co-crystallisation studies with JAK enzymes were used to increase potency and improve kinase selectivity of initial hits. Relevance of physicochemical properties in lung retention was then evaluated leading to the identification of potent and soluble inhibitors with long retention time in the lung and low systemic exposure. Among them, LAS194046 was selected for further profiling. LAS194046 is a potent and balanced pan-JAK inhibitor with an excellent physicochemical and ADME profile for inhaled administration. In addition, LAS194046 is not genotoxic and has limited off-target activities. LAS194046 has proven to be efficacious in animal models of respiratory diseases by inhaled route and has progressed to preclinical studies for the treatment of respiratory diseases such as asthma and COPD.

Discovery of LAS194046, a potent pan-JAK inhibitor for the inhaled treatment of respiratory diseases

255th National Meeting (2018)

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