Design of CNS-Permeable Agents for the Treatment of Lipid Storage Diseases

治疗脂质贮积病的中枢神经系统渗透剂的设计

• 批准号: 7934607
• 负责人: Scott D Larsen
• 金额: $ 22.75万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7934607
• 关键词: 1-Propanol; Anabolism; Area; Binding; Biological Assay; Blood - brain barrier anatomy; Bone Marrow Transplantation; Catabolism; Cells; Central Nervous System Agents; Ceramide glucosyltransferase; Characteristics; Computer Simulation; Development; Disease; Drug usage; Elements; Enzymes; Evaluation; Fabry Disease; Gaucher Disease; Gene Mutation; Glucosylceramides; Glycolipids; Glycoside Hydrolases; Glycosphingolipids; Homologous Gene; In Vitro; Left; Lipids; Lipoidosis; Lysosomal Storage Diseases; Mannose; Mediating; Michigan; Molecular Weight; Neuraxis; P-Glycoprotein; P-Glycoproteins; Patients; Penetration; Peripheral; Permeability; Phase II Clinical Trials; Plasma Proteins; Predisposition; Propanols; Property; Protein Binding; Proteins; Research Personnel; Sandhoff Disease; Series; Specificity; Sphingolipids; Surface; Testing; Tissues; Transferase; Universities; Work; analog; base; design; effective therapy; enzyme replacement therapy; gene therapy; glycosphingolipidoses; in vivo; inhibitor/antagonist; lysosomal proteins; pharmacophore; public health relevance; small molecule

DESCRIPTION (provided by applicant): Greater than seventy-five distinct lysosomal proteins have been characterized. Genetic mutations of forty-two of these proteins are associated with lysosomal storage diseases. Of these diseases, fourteen are the result of impaired catabolism of sphingolipids and seven of these are due to impaired degradation of glycosphingolipids. These disorders include type I Gaucher disease, Fabry disease, and various central nervous system based diseases. The traditional approach to the treatment of glycosphingolipidoses has been to use enzyme replacement therapy in the form of mannose terminated glycosidases. This strategy, although successful for the treatment of the peripheral manifestations of Fabry and Gaucher disease, is ineffective for CNS based disorders such as Tay-Sachs and Sandhoff disease. Other forms of enzyme replacement, including gene therapy and bone marrow transplantation have been disappointing to date. An alternative strategy has been the inhibition of glycosphingolipid biosynthesis by the use of small molecule inhibitors of glycosphingolipid transferases, most notably glucosylceramide synthase. The PDMP based glucosylceramide analogues represent the paradigm class of glucosylceramide synthase inhibitors. These compounds, discovered and characterized by the Shayman and Radin labs at the University of Michigan, have been widely used by many groups to probe the functions of glycolipids. One PDMP homologue, D-threo-ethylendioxyphenyl-2- octanoylamino-3-pyrrolidino-propanol, is currently in phase II trials for type I Gaucher disease. The PDMP homologues characterized to date, however, have demonstrated poor penetration of the CNS, limiting their potential utility to peripheral tissues. It is hypothesized that the existing PDMP class of potent glucosylceramide synthase inhibitors can be structurally modified to achieve penetration into the CNS without sacrificing key elements of the pharmacaphore. It is further hypothesized that the development of potent small molecule inhibitors of glucosylceramide synthase with efficient CNS permeability will significantly expand the scope of treatable glycosphingolipidoses. Toward these objectives, selected properties of the PDMP template (e.g. molecular weight, polar surface area and number of rotatable bonds) will be modified to more closely approximate those of CNS drugs, using computational models to guide the design. New compounds will be tested in both cell-free and whole cell assays for potency at inhibiting glycosphingolipid synthesis. Evaluations of passive cellular permeability, P-gp mediated efflux and plasma protein binding will be used to predict efficient CNS penetration and to prioritize compounds for in vivo testing. PUBLIC HEALTH RELEVANCE: Current therapy for rare but severely debilitating heritable lipid storage diseases is limited to peripheral tissues, leaving patients with CNS-based lipidoses, including Tay-Sachs, Fabry and Gaucher Types II and III, without effective treatment. Substrate reduction therapy via inhibition of glycosphingolipid biosynthesis holds promise for the treatment of CNS-based lipidoses if agents can be developed that efficiently penetrate the CNS. This proposal will evaluate the feasibility of modifying an established class of small molecule inhibitors of glucosylceramide synthase to achieve potency, specificity and blood brain barrier permeability.

描述（由申请人提供）：已对超过75种不同的溶酶体蛋白进行了表征。其中42种蛋白质的基因突变与溶酶体贮积病有关。在这些疾病中，有14种是鞘脂分解受损的结果，其中7种是由于鞘糖脂降解受损。这些疾病包括I型戈谢病、法布里病和各种基于中枢神经系统的疾病。治疗鞘糖脂病的传统方法是使用甘露糖终止的糖苷酶形式的酶替代疗法。该策略虽然成功治疗了法布里病和戈谢病的外周表现，但对基于CNS的疾病如泰-萨二氏病和桑德霍夫病无效。其他形式的酶替代，包括基因治疗和骨髓移植，迄今为止都令人失望。另一种策略是通过使用鞘糖脂转移酶的小分子抑制剂来抑制鞘糖脂的生物合成，最显著的是葡萄糖神经酰胺合酶。基于PdR的葡糖神经酰胺类似物代表葡糖神经酰胺合酶抑制剂的范例类别。这些化合物由密歇根大学的Shayman和Radin实验室发现并表征，已被许多团体广泛用于探测糖脂的功能。一种PdR同系物，D-苏式-亚乙基二氧基苯基-2-辛酰氨基-3-吡咯烷基-丙醇，目前正处于I型戈谢病的II期试验中。然而，迄今为止表征的PdR同源物已经证明了CNS的渗透性差，限制了它们对外周组织的潜在效用。据推测，现有的Pestival类有效的葡糖神经酰胺合酶抑制剂可以在结构上进行修饰，以实现渗透到CNS中，而不牺牲药效的关键要素。进一步假设，开发具有有效CNS渗透性的葡萄糖神经酰胺合酶强效小分子抑制剂将显著扩大可治疗鞘糖脂增多症的范围。为了实现这些目标，将使用计算模型来指导设计，对PdR模板的选定性质（例如分子量、极性表面积和可旋转键的数目）进行修改，以更接近CNS药物的性质。将在无细胞和全细胞试验中测试新化合物抑制鞘糖脂合成的效力。被动细胞渗透性、P-gp介导的外排和血浆蛋白结合的评价将用于预测有效的CNS渗透，并优先考虑用于体内试验的化合物。 公共卫生相关性：目前对罕见但严重衰弱的遗传性脂质储存疾病的治疗仅限于外周组织，使患者接受基于CNS的抗肿瘤剂量，包括Tay-Sachs、Fabry和Gaucher II型和III型，而没有有效的治疗。通过抑制鞘糖脂生物合成的底物减少疗法有望用于治疗基于CNS的药物，如果能够开发出有效渗透CNS的药物。该提案将评估修改葡萄糖神经酰胺合酶的已建立的小分子抑制剂类别以实现效力、特异性和血脑屏障通透性的可行性。