The discovery and characterization of leniolisib (CDZ173), a potent and selective inhibitor of Phosphoinositide 3-kinase delta (PI3Kd) will be presented. We report how innovative medicinal chemistry efforts led to the identification of a novel and promising tetrahydro-pyrido-pyrimidine lead series that could be rapidly further optimized into a favorable physicochemical space and resulted in the identification of leniolisib, currently in clinical development as an anti-inflammatory therapeutic agent. In vitro, leniolisib shows the capacity to inhibit a large spectrum of immune cell functions and in vivo, leniolisib inhibits B cell activation in rats and monkeys in a concentration- and time-dependent manner. In preclinical animal models, leniolisib potently inhibited the antibody production in response to immunization and reduced clinical symptoms in rat collagen-induced arthritis models. Structurally, leniolisib differs significantly from the first generation of PI3Kd and/or PI3Kgd-selective clinical compounds and, therefore, could differentiate favorably in its safety profile. First-in-human study indicated an excellent tolerability, favorable pharmacokinetic properties and a direct PK/PD relationship. A first clinical trial in patients suffering from APDS/PASLI, a rare disease caused by gain-of-function mutation of PI3Kd demonstrated that leniolisib was well tolerated and significantly improved laboratory and clinical parameters in APDS patients.

Discovery of leniolisib (CDZ173), a potent and selective new generation PI3Kdelta inhibitor for autoimmune and inflammatory diseases

256th National Meeting (2018)

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