PI3K delta is a lipid kinase which is expressed primarily in leukocytes. It plays a key role in immune cell signalling across a broad range of cell types and is activated in response to multiple triggers of relevance to respiratory disease. These include allergens, inflammatory cytokines, smoke and viruses. We believe that inhibitors of PI3K delta delivered directly to the lung, by the inhaled route, will therefore have therapeutic potential in the control of inflammatory processes leading to exacerbations associated with both asthma and COPD.This presentation will begin by describing the medicinal chemistry program around a series of indazole containing PI3K delta inhibitors, leading to highly potent and selective compounds with properties suitable for inhaled delivery. Medicinal chemistry considerations specific to the development of an inhaled candidate compound will be discussed, along with hypotheses for the exquisite PI3K isoform selectivity observed in this series. The importance of crystallography and modelling in interpreting SAR and driving compound design will also be highlighted.The biological profile of the resulting clinical candidate, Compound A, will be presented, including reduction of cytokine release from stimulated human lung tissue in vitro and prevention of inflammatory responses associated with allergic airway inflammation in rats. Recent data showing the potential for a PI3K delta inhibitor to complement inhaled steroids in the treatment of asthma and COPD patients will also be discussed.

Discovery of potent and selective PI3K delta inhibitors for the treatment of respiratory indications

245th National Meeting (2013)

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