title: Discovery of a Potent, Selective, and Orally Available PI3Kδ Inhibitor for the Treatment of Inflammatory Diseases.
abstract: 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.
authors.affiliation: Medicinal Chemistry and Screening, Pharmacokinetics and Metabolism, Systems Biology, and Respiratory Therapeutic Area, Almirall R&D , Barcelona 08980, Spain.
authors.forename: Montse
authors.initials: M
authors.lastname: Erra
authors.affiliation: Medicinal Chemistry and Screening, Pharmacokinetics and Metabolism, Systems Biology, and Respiratory Therapeutic Area, Almirall R&D , Barcelona 08980, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Taltavull
authors.affiliation: Medicinal Chemistry and Screening, Pharmacokinetics and Metabolism, Systems Biology, and Respiratory Therapeutic Area, Almirall R&D , Barcelona 08980, Spain.
authors.forename: Angelique
authors.initials: A
authors.lastname: Gréco
authors.affiliation: Medicinal Chemistry and Screening, Pharmacokinetics and Metabolism, Systems Biology, and Respiratory Therapeutic Area, Almirall R&D , Barcelona 08980, Spain.
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Bernal
authors.affiliation: Medicinal Chemistry and Screening, Pharmacokinetics and Metabolism, Systems Biology, and Respiratory Therapeutic Area, Almirall R&D , Barcelona 08980, Spain.
authors.forename: Juan Francisco
authors.initials: JF
authors.lastname: Caturla
authors.affiliation: Medicinal Chemistry and Screening, Pharmacokinetics and Metabolism, Systems Biology, and Respiratory Therapeutic Area, Almirall R&D , Barcelona 08980, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Gràcia
authors.affiliation: Medicinal Chemistry and Screening, Pharmacokinetics and Metabolism, Systems Biology, and Respiratory Therapeutic Area, Almirall R&D , Barcelona 08980, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Domínguez
authors.affiliation: Medicinal Chemistry and Screening, Pharmacokinetics and Metabolism, Systems Biology, and Respiratory Therapeutic Area, Almirall R&D , Barcelona 08980, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Sabaté
authors.affiliation: Medicinal Chemistry and Screening, Pharmacokinetics and Metabolism, Systems Biology, and Respiratory Therapeutic Area, Almirall R&D , Barcelona 08980, Spain.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Paris
authors.affiliation: Medicinal Chemistry and Screening, Pharmacokinetics and Metabolism, Systems Biology, and Respiratory Therapeutic Area, Almirall R&D , Barcelona 08980, Spain.
authors.forename: Salomé
authors.initials: S
authors.lastname: Soria
authors.affiliation: Medicinal Chemistry and Screening, Pharmacokinetics and Metabolism, Systems Biology, and Respiratory Therapeutic Area, Almirall R&D , Barcelona 08980, Spain.
authors.forename: Begoña
authors.initials: B
authors.lastname: Hernández
authors.affiliation: Medicinal Chemistry and Screening, Pharmacokinetics and Metabolism, Systems Biology, and Respiratory Therapeutic Area, Almirall R&D , Barcelona 08980, Spain.
authors.forename: Clara
authors.initials: C
authors.lastname: Armengol
authors.affiliation: Medicinal Chemistry and Screening, Pharmacokinetics and Metabolism, Systems Biology, and Respiratory Therapeutic Area, Almirall R&D , Barcelona 08980, Spain.
authors.forename: Judit
authors.initials: J
authors.lastname: Cabedo
authors.affiliation: Medicinal Chemistry and Screening, Pharmacokinetics and Metabolism, Systems Biology, and Respiratory Therapeutic Area, Almirall R&D , Barcelona 08980, Spain.
authors.forename: Mónica
authors.initials: M
authors.lastname: Bravo
authors.affiliation: Medicinal Chemistry and Screening, Pharmacokinetics and Metabolism, Systems Biology, and Respiratory Therapeutic Area, Almirall R&D , Barcelona 08980, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Calama
authors.affiliation: Medicinal Chemistry and Screening, Pharmacokinetics and Metabolism, Systems Biology, and Respiratory Therapeutic Area, Almirall R&D , Barcelona 08980, Spain.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Miralpeix
authors.affiliation: Medicinal Chemistry and Screening, Pharmacokinetics and Metabolism, Systems Biology, and Respiratory Therapeutic Area, Almirall R&D , Barcelona 08980, Spain.
authors.forename: Martin D
authors.initials: MD
authors.lastname: Lehner
keywords: PI3Kδ inhibitor; Phosphoinositide-3-kinase delta inhibitor; autoimmune diseases; inflammatory diseases; lead optimization; structure−activity relationship