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, 8 (1), 118-123
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Discovery of a Potent, Selective, and Orally Available PI3Kδ Inhibitor for the Treatment of Inflammatory Diseases

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

Montse Erra et al. ACS Med Chem Lett.

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.

Conflict of interest statement

The authors declare no competing financial interest.

Figures

Scheme 1
Scheme 1. Pyrrolotriazinone Scaffold
Figure 1
Figure 1
X-ray cocrystal structure of the binding pocket surface of human PI3Kδ containing compound 11.
Figure 2
Figure 2
Inhibition of ConA induced increase in IL-2 levels in rat plasma of LAS191954 vs reference compound Idelalisib.
Figure 3
Figure 3
Inhibition of OVA BAL cell accumulation in BN rats at 24 h by twice daily doses of LAS191954 and Idelalisib.

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