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）：超过75种溶酶体蛋白已被鉴定，其中42种蛋白的基因突变导致临床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的结果，8种是由于鞘脂糖降解受损。治疗这些疾病的传统方法是通过使用甘露糖或甘露糖-6-磷酸终止重组蛋白作为酶替代疗法的基础。另一种治疗1型戈谢病的方法是使用合成抑制疗法，目前已被临床证实。通过靶向鞘糖脂合成的第一步，