In vivo proof of efficacy studies for a novel glucosylceramide synthase inhibitor

新型葡萄糖神经酰胺合酶抑制剂的体内功效研究证据

• 批准号: 8355938
• 负责人: JAMES ALAN SHAYMAN
• 金额: $ 19.44万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8355938
• 关键词: ABCB1 gene; Acetamides; Affect; Area; Biological Assay; Biological Availability; Blood; Blood - brain barrier anatomy; Brain; Catabolism; Ceramide glucosyltransferase; Cessation of life; Clinical; Deterioration; Development; Dioxins; Disease; Dose; Drug Formulations; Drug Kinetics; Excretory function; Exploratory/Developmental Grant for Diagnostic Cancer Imaging; Fabry Disease; Funding; Gangliosidosis GM1; Gaucher Disease; Gene Mutation; Glucosylceramides; Glycosphingolipids; Grant; Half-Life; Human; Inflammatory; Inherited; Lead; Lysosomal Storage Diseases; Mannose; Measurement; Metabolism; Modeling; Multi-Drug Resistance; Mus; Neurologic; Non-Neuronopathic Gaucher Disease; Oral; Pathway interactions; Peripheral; Pharmaceutical Preparations; Pharmacy facility; Phase II Clinical Trials; Principal Investigator; Property; Proteins; Rare Diseases; Recombinant Proteins; Research Design; Series; Sodium Chloride; Sphingolipids; Subacute Neuronopathic Gaucher Disease; Surface; Tartrates; Tay-Sachs Disease; Testing; Tissues; Wild Type Mouse; Work; analog; base; brain tissue; college; design; drug candidate; enzyme replacement therapy; glycosphingolipidoses; imiglucerase; in vitro Assay; in vivo; inhibitor/antagonist; lysosomal proteins; mannose 6 phosphate; mouse model; novel; pharmacophore; phase 3 study; prevent; small molecule

DESCRIPTION (provided by applicant): Greater than 75 lysosomal proteins have been characterized, and genetic mutations in 42 of these proteins result in clinically unique lysosomal storage diseases. Of these disorders, 14 are the result of impaired catabolism of sphingolipids and 8 are due to the impaired degradation of glycosphingolipids. The traditional approach for treating these disorders has been through the use of mannose or mannose-6-phosphate terminated recombinant proteins as the basis for enzyme replacement therapy. An alternative approach, now clinically proven for the treatment of type 1 Gaucher disease, is the use of synthesis inhibition therapy. By targeting the first synthetic step in glycosphingolipid synthesis, glucosylceramide synthase, potent small molecule inhibitors were designed as highly active lead compounds for the treatment of Gaucher type 1 and Fabry disease. One compound in this series, eliglustat tartrate, has been demonstrated to be as efficacious as imiglucerase in phase 2 trials and is currently the basis for two phase 3 studies for type 1 Gaucher disease. Because eliglustat tartrate does not cross the blood brain barrier, it is unsuitable for the treatment of several glycosphingolipidoses with CNS involvement that include types 2 and 3 Gaucher disease, early and late onset Tay-Sachs disease, and GM1 gangliosidosis. With funding from a prior R21 award, the applicants undertook the property-based design of inhibitors of glucosylceramide synthase that lack recognition by the multidrug resistance transporter MDR1 utilizing the previously defined pharmacophore for eliglustat tartrate. Using considerations of conformational mobility and topological polar surface area, an analog of eliglustat was identified that retained activity against glucosylceramide synthase in the low nanomolar range, lacked recognition by MDR1 in two in vitro assays, and was shown to lower brain glucosylceramide levels in wild type mice with short term dosing. We now propose to study this compound, 2-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-(2,3- dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide (CCG-203586), in a suitable mouse model of type 3 Gaucher disease to ascertain whether it is an appropriate candidate for clinical development. The following hypothesis is to be tested. CCG-203586 will delay or prevent the onset of neurological deterioration and death in models of the neuronopathic Gaucher mouse. The specific aims of this project include the following: 1. To ascertain the optimal formulation of CCG-203586 for oral dosing. 2. To establish an assay for the measurement of CCG-203586 in blood and tissues, including brain. 3. To perform pharmacokinetic studies in wild type mice to determine the bioavailability, half-life, distribution, metabolism, and excretion of CCG-203586. 4. To treat the neuronopathic Gaucher mice with CCG-203586 either orally or parenterally to determine its efficacy in lowering peripheral tissue and brain glucosylceramide accumulation, delaying or preventing death, preventing histopathological changes in the brain, and inflammatory changes in the brain and peripheral tissues.

描述（由申请人提供）：超过 75 种溶酶体蛋白已得到表征，其中 42 种蛋白的基因突变导致临床上独特的溶酶体贮积病。在这些疾病中，14 种是鞘脂分解代谢受损所致，8 种是鞘糖脂降解受损所致。治疗这些疾病的传统方法是使用甘露糖或甘露糖-6-磷酸封端的重组蛋白作为酶替代疗法的基础。另一种方法是使用合成抑制疗法，现已被临床证明可用于治疗 1 型戈谢病。通过针对鞘糖脂合成的第一步， 葡萄糖神经酰胺合酶，强效小分子抑制剂，被设计为高活性先导化合物，用于治疗戈谢 1 型和法布里病。该系列中的一种化合物，eliglustat tartrate，已在 2 期试验中被证明与伊米苷酶一样有效，目前是 1 型戈谢病的两项 3 期研究的基础。由于酒石酸 Eliglustat 不能穿过血脑屏障，因此不适合治疗几种累及 CNS 的鞘糖脂沉积症，包括 2 型和 3 型戈谢病、早发型和晚发型 Tay-Sachs 病以及 GM1 神经节苷脂沉积症。在先前 R21 奖项的资助下，申请人利用先前定义的酒石酸 Eliglustat 药效团，进行了基于特性的葡萄糖神经酰胺合酶抑制剂的设计，该抑制剂缺乏多药耐药性转运蛋白 MDR1 的识别。考虑到构象迁移率和拓扑极性表面积，发现了一种 Eliglustat 类似物，它在低纳摩尔范围内保留了针对葡萄糖神经酰胺合酶的活性，在两项体外试验中缺乏 MDR1 的识别，并且被证明可以在短期给药的野生型小鼠中降低脑葡萄糖神经酰胺水平。我们现在建议研究这种化合物，2-(2,3-二氢-1H-茚-2-基)-N-((1R,2R)-1-(2,3-二氢苯并[b][1,4]二恶英-6-基)-1-羟基-3-(吡咯烷-1-基)丙-2-基)乙酰胺(CCG-203586)， 在合适的 3 型戈谢病小鼠模型中进行试验，以确定其是否适合临床开发。有待检验以下假设。 CCG-203586 将延迟或预防神经病性戈谢小鼠模型中神经功能恶化和死亡的发生。该项目的具体目标包括以下内容： 1. 确定 CCG-203586 口服给药的最佳配方。 2. 建立一种测定血液和组织（包括脑）中 CCG-203586 的方法。 3. 在野生型小鼠中进行药代动力学研究，以确定CCG-203586的生物利用度、半衰期、分布、代谢和排泄。 4.用CCG-203586口服或肠胃外治疗神经病性戈谢小鼠，以确定其在降低外周组织和脑葡萄糖神经酰胺积累、延迟或预防死亡、预防脑组织病理学变化以及脑和外周组织炎症变化方面的功效。