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Discovery of CDZ173 (Leniolisib), Representing a Structurally Novel Class of PI3K Delta-Selective Inhibitors
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2017-09-05 00:00:00 , DOI: 10.1021/acsmedchemlett.7b00293 Klemens Hoegenauer 1 , Nicolas Soldermann 1 , Frédéric Zécri 1 , Ross S. Strang 1 , Nadege Graveleau 1 , Romain M. Wolf 1 , Nigel G. Cooke 1 , Alexander B. Smith 1 , Gregory J. Hollingworth 1 , Joachim Blanz 1 , Sascha Gutmann 1 , Gabriele Rummel 1 , Amanda Littlewood-Evans 1 , Christoph Burkhart 1
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2017-09-05 00:00:00 , DOI: 10.1021/acsmedchemlett.7b00293 Klemens Hoegenauer 1 , Nicolas Soldermann 1 , Frédéric Zécri 1 , Ross S. Strang 1 , Nadege Graveleau 1 , Romain M. Wolf 1 , Nigel G. Cooke 1 , Alexander B. Smith 1 , Gregory J. Hollingworth 1 , Joachim Blanz 1 , Sascha Gutmann 1 , Gabriele Rummel 1 , Amanda Littlewood-Evans 1 , Christoph Burkhart 1
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The predominant expression of phosphoinositide 3-kinase δ (PI3Kδ) 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 PI3Kδ should avoid potential side effects associated with the ubiquitously expressed PI3Kα and β 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 PI3Kδ 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 PI3Kδ and PI3Kγδ-selective clinical compounds. Therefore, CDZ173 could differentiate by a more favorable safety profile. CDZ173 is currently in clinical studies in patients suffering from primary Sjögren’s syndrome and in APDS/PASLI, a disease caused by gain-of-function mutations of PI3Kδ.
中文翻译：
发现CDZ173（Leniolisib），代表结构上新型的PI3K Delta选择抑制剂
磷酸肌醇3激酶δ（PI3Kδ）在白细胞中的主要表达及其在B和T细胞功能中的关键作用导致以下假设：该同种型的选择性抑制剂可能具有作为治疗变应性和炎性疾病的潜力。专门针对PI3Kδ应当避免与普遍表达的PI3Kα和β同工型相关的潜在副作用。我们公开了如何将先前发现的4,6-二芳基喹唑啉的杂环核心转变为亲脂性较低的5,6,7,8-四氢吡啶并[4,3- d]嘧啶，然后用吡咯烷-3-胺取代苯基之一，得到的化合物系列具有最佳的靶标分布和良好的ADME性能。最终的亲脂性调节导致发现CDZ173（leniolisib），一种有效的PI3Kδ选择性抑制剂，具有合适的特性和功效，可作为抗炎治疗剂用于临床开发。在体外，CDZ173可抑制多种免疫细胞功能，如B细胞和T细胞，嗜中性粒细胞，单核细胞，嗜碱性粒细胞，浆细胞样树突状细胞和肥大细胞中所示。体内，CDZ173以浓度和时间依赖性方式抑制大鼠和猴子的B细胞活化。预防性或治疗性给药后，CDZ173在大鼠胶原蛋白诱发的关节炎模型中有效抑制抗原特异性抗体的产生并减轻疾病症状。从结构上讲，CDZ173与第一代PI3Kδ和PI3Kγδ选择性临床化合物明显不同。因此，CDZ173可以通过更有利的安全性来区分。CDZ173目前正在针对患有原发性干燥综合征的患者以及APDS / PASLI（由PI3Kδ功能获得性突变引起的疾病）进行临床研究。
更新日期：2017-09-05
中文翻译：
发现CDZ173（Leniolisib），代表结构上新型的PI3K Delta选择抑制剂
磷酸肌醇3激酶δ（PI3Kδ）在白细胞中的主要表达及其在B和T细胞功能中的关键作用导致以下假设：该同种型的选择性抑制剂可能具有作为治疗变应性和炎性疾病的潜力。专门针对PI3Kδ应当避免与普遍表达的PI3Kα和β同工型相关的潜在副作用。我们公开了如何将先前发现的4,6-二芳基喹唑啉的杂环核心转变为亲脂性较低的5,6,7,8-四氢吡啶并[4,3- d]嘧啶，然后用吡咯烷-3-胺取代苯基之一，得到的化合物系列具有最佳的靶标分布和良好的ADME性能。最终的亲脂性调节导致发现CDZ173（leniolisib），一种有效的PI3Kδ选择性抑制剂，具有合适的特性和功效，可作为抗炎治疗剂用于临床开发。在体外，CDZ173可抑制多种免疫细胞功能，如B细胞和T细胞，嗜中性粒细胞，单核细胞，嗜碱性粒细胞，浆细胞样树突状细胞和肥大细胞中所示。体内，CDZ173以浓度和时间依赖性方式抑制大鼠和猴子的B细胞活化。预防性或治疗性给药后，CDZ173在大鼠胶原蛋白诱发的关节炎模型中有效抑制抗原特异性抗体的产生并减轻疾病症状。从结构上讲，CDZ173与第一代PI3Kδ和PI3Kγδ选择性临床化合物明显不同。因此，CDZ173可以通过更有利的安全性来区分。CDZ173目前正在针对患有原发性干燥综合征的患者以及APDS / PASLI（由PI3Kδ功能获得性突变引起的疾病）进行临床研究。
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