Silent Allosteric Modulation of mGluR5 for Safe and Effective Therapy of Alzheimer's Disease

总结 该项目旨在开发一种用于阿尔茨海默病（AD）的新型疾病修饰化合物。突触丢失 在AD大脑中，与认知症状密切相关，最初由淀粉样蛋白β（AAPs）触发 肽积累。我们已经描述了一种途径，在该途径中，可溶性的ApoA寡聚体与朊病毒蛋白结合，从而 接合mGluR 5作为共受体，并激活PTK 2B（Pyk 2）和Fyn激酶以与Tau病理学偶联 和突触缺失mGluR 5是一种GPCR，多个研究小组已经表明，中断mGluR 5功能 挽救临床前AD表型，使其成为有吸引力的药物靶点。然而，mGluR 5具有生理上的 作为谷氨酸受体的作用，完全抑制会损害功能。因此，典型的拮抗剂具有狭窄的 治疗窗口 耶鲁大学已经获得了一个广泛的mGluR 5指导的化合物库的独家许可， 知识产权保护。在这些化学品中，我们发现了一种高效的，口服生物可利用的 mGluR 5配体，其不改变基础或谷氨酸活性，但确实阻断mGluR 5的A β o/PrPC活化。 该化合物被认为是mGluR 5的沉默变构调节剂或SAM，意思是关于mGluR 5的“沉默”。 谷氨酸盐，而对Aßo/PrPC具有拮抗作用。初步研究表明，这种药物具有强大的疗效， 用于多种临床前小鼠AD表型的SAM化合物。药物治疗恢复了突触密度， 恢复LTP并将内存性能恢复到WT级别。虽然密切相关的mGluR 5配体具有 广泛的选择性和DMPK数据，这些在早期阶段尚未开发用于SAM化合物， 我们建议在这里为这位主要候选人获得它们。总体目标是开发疾病修饰 口服治疗有效减缓、停止或部分逆转MCI状态和轻度痴呆中的AD进展。

SUMMARY This project seeks to develop a novel disease-modifying compound for Alzheimer’s disease (AD). Synapse loss in AD brain has been tightly correlated with cognitive symptoms and is triggered initially by amyloid beta (Aß) peptide accumulation. We have described a pathway in which soluble Aß oligomers bind to Prion Protein, thereby engaging mGluR5 as a co-receptor, and activating PTK2B (Pyk2) and Fyn kinases to couple with Tau pathology and synapse loss. mGluR5 is a GPCR, and multiple groups have shown that interrupting mGluR5 function rescues preclinical AD phenotypes, making it an attractive drug target. However, mGluR5 has a physiological role as a glutamate receptor and full inhibition impairs function. Consequently, typical antagonists have a narrow therapeutic window. Yale has obtained an exclusive license to an extensive mGluR5-directed compound library with robust Intellectual Property protection. Within this chemical collection, we identified a highly potent, orally bioavailable mGluR5 ligand that does not alter basal or glutamate activity, but does block Aßo/PrPC activation of mGluR5. This compound is considered a silent allosteric modulator, or SAM, for mGluR5, meaning “silent” with regard to glutamate, while antagonistic with regard to Aßo/PrPC. Preliminary studies demonstrate robust efficacy of this SAM compound for multiple preclinical mouse AD phenotypes. Drug treatment recovers synapse density, restores LTP and returns memory performance to WT levels. While closely related mGluR5 ligands have extensive selectivity and DMPK data, these are not yet developed for the SAM compound at this Early Stage, and we propose to obtain them here for this lead candidate. The overall goal is to develop disease-modifying oral therapy effective to slow, halt or partially reverse AD progression both in the MCI state and in mild dementia.