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LAS191954 Sale

(Synonyms: 暂无) 目录号 : GC36426

LAS191954 是有效的、选择性的、口服有效的 PI3Kδ 的抑制剂,可用于炎症相关疾病的研究,其 IC50 值为 2.6 nM。

LAS191954 Chemical Structure

Cas No.:1403947-26-1

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产品描述

LAS191954 is a potent, selective and orally active PI3Kδ inhibitor for inflammatory diseases treatment, with an IC50 of 2.6 nM[1]. PI3Kδ|2.6 nM (IC50)

[1]. Erra M, et al. 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.

Chemical Properties

Cas No. 1403947-26-1 SDF
别名 暂无
Canonical SMILES O=C1N(C2=CC=CC=C2)C([C@@H](NC3=C(C#N)C(N)=NC=N3)C)=NN4C1=C(C#N)C=C4
分子式 C20H15N9O 分子量 397.39
溶解度 Soluble in DMSO 储存条件 Store at -20°C
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1 mM 2.5164 mL 12.5821 mL 25.1642 mL
5 mM 0.5033 mL 2.5164 mL 5.0328 mL
10 mM 0.2516 mL 1.2582 mL 2.5164 mL
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Research Update

Therapeutic Effect of a Novel Phosphatidylinositol-3-Kinase δ Inhibitor in Experimental Epidermolysis Bullosa Acquisita

Front Immunol 2018 Jul 12;9:1558.PMID:30050528DOI:10.3389/fimmu.2018.01558.

Epidermolysis bullosa acquisita (EBA) is a rare, but prototypical, organ-specific autoimmune disease, characterized and caused by autoantibodies against type VII collagen (COL7). Mucocutaneous inflammation, blistering, and scarring are the clinical hallmarks of the disease. Treatment of EBA is difficult and mainly relies on general immunosuppression. Hence, novel treatment options are urgently needed. The phosphatidylinositol-3-kinase (PI3K) pathway is a putative target for the treatment of inflammatory diseases, including EBA. We recently discovered LAS191954, an orally available, selective PI3Kδ inhibitor. PI3Kδ has been shown to be involved in B cell and neutrophil cellular functions. Both cell types critically contribute to EBA pathogenesis, rendering LAS191954 a potential drug candidate for EBA treatment. We, here, demonstrate that LAS191954, when administered chronically, dose-dependently improved the clinical phenotype of mice harboring widespread skin lesions secondary to immunization-induced EBA. Direct comparison with high-dose corticosteroid treatment indicated superiority of LAS191954. Interestingly, levels of circulating autoantibodies were unaltered in all groups, indicating a mode of action independent of the inhibition of B cell function. In line with this, LAS191954 also hindered disease progression in antibody transfer-induced EBA, where disease develops dependent on myeloid, but independent of B cells. We further show that, in vitro, LAS191954 dose-dependently impaired activation of human myeloid cells by relevant disease stimuli. Specifically, immune complex-mediated and C5a-mediated ROS release were inhibited in a PI3Kδ-dependent manner. Accordingly, LAS191954 also modulated the dermal-epidermal separation induced in vitro by co-incubation of immune complexes with polymorph nuclear cells, thus pointing to an important role of PI3Kδ in EBA effector functions. Altogether, these results suggest a new potential mechanism for the treatment of EBA and potentially also other autoimmune bullous 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.PMID:28105286DOI:10.1021/acsmedchemlett.6b00438.

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.