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

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

  • ACS Med Chem Lett. 2016 Nov 30;8(1):118-123. doi: 10.1021/acsmedchemlett.6b00438.
Montse Erra 1,  Joan Taltavull 1,  Angelique Gréco 1,  Francisco Javier Bernal 1,  Juan Francisco Caturla 1,  Jordi Gràcia 1,  María Domínguez 1,  Mar Sabaté 1,  Stéphane Paris 1,  Salomé Soria 1,  Begoña Hernández 1,  Clara Armengol 1,  Judit Cabedo 1,  Mónica Bravo 1,  Elena Calama 1,  Montserrat Miralpeix 1,  Martin D Lehner 1
Affiliations

Affiliation

  • 1 Medicinal Chemistry and Screening, Pharmacokinetics and Metabolism, Systems Biology, and Respiratory Therapeutic Area, Almirall R&D , Barcelona 08980, Spain.
PMID: 28105286 DOI: 10.1021/acsmedchemlett.6b00438
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.

Keywords

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

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