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

摘要 该项目旨在开发一种新的治疗阿尔茨海默病(AD)的药物。突触丢失 在阿尔茨海默病中，大脑与认知症状密切相关，最初由淀粉样β蛋白(Aü)触发 多肽积累。我们已经描述了一种途径，在该途径中，可溶寡聚体与Prion蛋白结合，从而 结合mGluR5作为共受体，激活PTK2B(Pyk2)和Fyn激酶与Tau病理偶联 和突触丢失。MGluR5是一种GPCR，多个小组已经证明，干扰mGluR5的功能 挽救临床前AD表型，使其成为有吸引力的药物靶点。然而，mGluR5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，典型的对手有一个狭窄的 治疗窗口。 耶鲁大学已经获得了广泛的mGluR5指导的复合库的独家许可，该库具有强大的 知识产权保护。在这个化学收集中，我们确定了一种高度有效的口服生物利用度 MGluR5配体，不改变基础或谷氨酸活性，但阻断mGluR5的A？o/PrPC激活。 这种化合物被认为是mGluR5的无声变构调节剂，或SAM，意思是关于 谷氨酸，而对A？o/PrPC有拮抗作用。初步研究表明，这种方法具有很强的疗效。 SAM化合物用于多种临床前小鼠AD表型。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。而密切相关的mGluR5配体 广泛的选择性和DMPK数据，这些数据在这个早期阶段还没有为SAM化合物开发， 我们建议在这里为这位主要候选人获得这些证书。总体目标是开发治疗疾病的药物 口服疗法在MCI状态和轻度痴呆中都能有效地减缓、停止或部分逆转AD的进展。

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.