Discovery of CDZ173 (Leniolisib), Representing a Structurally Novel Class of PI3K Delta-Selective Inhibitors.

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Hoegenauer K, Soldermann N, Zecri F, Strang RS, Graveleau N, Wolf RM, Cooke NG, Smith AB, Hollingworth GJ, Blanz J, Gutmann S, Rummel G, Littlewood-Evans A, Burkhart C

Discovery of CDZ173 (Leniolisib), Representing a Structurally Novel Class of PI3K Delta-Selective Inhibitors.

ACS Med Chem Lett. 2017 Aug 25;8(9):975-980. doi: 10.1021/acsmedchemlett.7b00293. eCollection 2017 Sep 14.

PubMed ID

28947947 [ View in PubMed

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Abstract

The predominant expression of phosphoinositide 3-kinase delta (PI3Kdelta) in leukocytes and its critical role in B and T cell functions led to the hypothesis that selective inhibitors of this isoform would have potential as therapeutics for the treatment of allergic and inflammatory disease. Targeting specifically PI3Kdelta should avoid potential side effects associated with the ubiquitously expressed PI3Kalpha and beta isoforms. We disclose how morphing the heterocyclic core of previously discovered 4,6-diaryl quinazolines to a significantly less lipophilic 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine, followed by replacement of one of the phenyl groups with a pyrrolidine-3-amine, led to a compound series with an optimal on-target profile and good ADME properties. A final lipophilicity adjustment led to the discovery of CDZ173 (leniolisib), a potent PI3Kdelta selective inhibitor with suitable properties and efficacy for clinical development as an anti-inflammatory therapeutic. In vitro, CDZ173 inhibits a large spectrum of immune cell functions, as demonstrated in B and T cells, neutrophils, monocytes, basophils, plasmocytoid dendritic cells, and mast cells. In vivo, CDZ173 inhibits B cell activation in rats and monkeys in a concentration- and time-dependent manner. After prophylactic or therapeutic dosing, CDZ173 potently inhibited antigen-specific antibody production and reduced disease symptoms in a rat collagen-induced arthritis model. Structurally, CDZ173 differs significantly from the first generation of PI3Kdelta and PI3Kgammadelta-selective clinical compounds. Therefore, CDZ173 could differentiate by a more favorable safety profile. CDZ173 is currently in clinical studies in patients suffering from primary Sjogren's syndrome and in APDS/PASLI, a disease caused by gain-of-function mutations of PI3Kdelta.

DrugBank Data that Cites this Article

Drugs

Leniolisib

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Leniolisib	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform	Protein	Humans	Yes	Inhibitor	Details