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: 8500485
• 负责人: JAMES ALAN SHAYMAN
• 金额: $ 22.51万
• 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 2014-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8500485
• 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）：已经表征了超过75种溶酶体蛋白，其中42种这些蛋白质的遗传突变导致临床独特的溶酶体储存疾病。在这些疾病中，有14个是鞘脂的分解代谢受损的结果，是由于糖磷脂脂的降解受损所致。治疗这些疾病的传统方法是通过使用甘露糖或甘露糖 - 6-磷酸盐终止重组蛋白作为酶替代疗法的基础。一种替代方法，如今已在临床上被证明用于治疗1型Gaucher病，是使用合成抑制疗法。通过靶向糖脂合成中的第一个合成步骤， 葡萄糖基酰胺合酶，有效的小分子抑制剂被设计为高度活性的铅化合物，用于治疗1型高雪剂和法布里病。该系列中的一种化合物是Eliglustat Tartrate，在2阶段试验中已被证明与Imiglucerase一样有效，目前是对1型Gaucher病的两阶段研究的基础。由于Eliglustat tartrate并未越过血脑屏障，因此不适合将几种糖磷脂与中枢神经系统介入（包括2型和3型Gaucher病），早期和晚期发作Tay-Sachs病和GM1恒河疾病的治疗。通过先前的R21奖的资金，申请人进行了基于属性的葡萄糖基酶合酶抑制剂的设计，该设计利用了先前定义的对Eliglustat tartrate的药效团的多药耐药性转运蛋白MDR1的识别。利用构象迁移率和拓扑极性表面积的考虑，鉴定出eliglustat的类似物在低纳摩尔范围内保留了针对葡萄糖基酰胺合酶的活性，在两个体外测定中缺乏MDR1的识别，并且被证明可在短期剂量剂量的野生型小鼠中降低脑葡萄糖酰胺水平。现在，我们建议研究这种化合物，2-（2,3-二氢-1H-Inden-2--2-基）-N- - （（（1r，2r）-1-（2,3-二氢苯甲酸[b] [1,4]二氧蛋白-6-6-6-基）-1-羟基-3-3-（pyrRolidIdin-c-yyl）acciN-c-cican-cacy（pyrroliidgy）acciTAN（CIT）accan-cican-cican-cic accIDAM（CICEN）-CICEN（CICEN）accIDEAN（CICEN）accIDEAN（CICEN）accIDAM）在适当的3型Gaucher疾病的小鼠模型中，确定它是否是临床发育的合适候选者。要检验以下假设。 CCG-203586将延迟或防止神经疾病Gaucher小鼠模型中神经系统恶化和死亡的发作。该项目的具体目的包括：1。确定口服剂量CCG-203586的最佳配方。 2。建立用于测量包括大脑在内的血液和组织中CCG-203586的测定法。 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治疗神经疾病的Gaucher小鼠，无论是口服还是肠胃外，都可以确定其在降低外周组织组织和脑葡萄糖基辛基酰胺的积累，延迟或预防死亡，防止大脑的组织病理学变化以及脑和外围组织的炎症变化的功效。