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Discovery of a Potent, Selective, and Orally Available PI3K? Inhibitor for the Treatment of Inflammatory Diseases.

ABSTRACT: The delta isoform of the phosphatidylinositol 3-kinase (PI3K?) 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 PI3K? 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.

SUBMITTER: Erra M

PROVIDER: S-EPMC5238472 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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

Erra Montse M Taltavull Joan J Gréco Angelique A Bernal Francisco Javier FJ Caturla Juan Francisco JF Gràcia Jordi J Domínguez María M Sabaté Mar M Paris Stéphane S Soria Salomé S Hernández Begoña B Armengol Clara C Cabedo Judit J Bravo Mónica M Calama Elena E Miralpeix Montserrat M Lehner Martin D MD

ACS medicinal chemistry letters 20161130 1

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 ...[more]

PMID: 28105286

Dataset Information

Discovery of a Potent, Selective, and Orally Available PI3K? Inhibitor for the Treatment of Inflammatory Diseases.

Publications

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

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