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ACS Med Chem Lett. 2016 Nov 30;8(1):118-123. doi: 10.1021/acsmedchemlett.6b00438. eCollection 2017 Jan 12.

Discovery of a Potent, Selective, and Orally Available PI3Kδ Inhibitor for the Treatment of Inflammatory Diseases.

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Medicinal Chemistry and Screening, Pharmacokinetics and Metabolism, Systems Biology, and Respiratory Therapeutic Area, Almirall R&D , Barcelona 08980, Spain.


The delta isoform of the phosphatidylinositol 3-kinase (PI3Kδ) has been shown to have an essential role in specific immune cell functions and thus represents a potential therapeutic target for autoimmune and inflammatory diseases. Herein, the optimization of a series of pyrrolotriazinones as potent and selective PI3Kδ inhibitors is described. The main challenge of the optimization process was to identify an orally available compound with a good pharmacokinetic profile in preclinical species that predicted a suitable dosing regimen in humans. Structure-activity relationships and structure-property relationships are discussed. This medicinal chemistry exercise led to the identification of LAS191954 as a candidate for clinical development.


PI3Kδ inhibitor; Phosphoinositide-3-kinase delta inhibitor; autoimmune diseases; inflammatory diseases; lead optimization; structure−activity relationship

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