Ratni Hasane, Alker Andre, Bartels Bjoern, Bissantz Caterina, Chen Weichun, Gerlach Irene, Limberg Anja, Lu Mingqiu, Neidhart Werner, Pichereau Solen, Reutlinger Michael, Rodriguez-Sarmiento Rosa-Maria, Jakob-Roetne Roland, Schmitt Georg, Zhang Eric, Baumann Karlheinz
F. Hoffmann-La Roche Ltd., pRED, Pharma Research & Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070 Basel, Switzerland.
F. Hoffmann-La Roche Ltd., pRED, Pharma Research & Early Development, Roche Innovation Center Shanghai, Cai Lun Road 720, 201203 Shanghai, China.
ACS Med Chem Lett. 2020 Apr 27;11(6):1257-1268. doi: 10.1021/acsmedchemlett.0c00109. eCollection 2020 Jun 11.
γ-Secretase (GS) is a key target for the potential treatment of Alzheimer's disease. While inhibiting GS led to serious side effects, its modulation holds a lot of potential to deliver a safe treatment. Herein, we report the discovery of a potent and selective gamma secretase modulator (GSM) ()- (RO7185876), belonging to a novel chemical class, the triazolo-azepines. This compound demonstrates an excellent in vitro and in vivo DMPK profile. Furthermore, based on its in vivo efficacy in a pharmacodynamic mouse model and the outcome of the dose range finding (DRF) toxicological studies in two species, this compound was selected to undergo entry in human enabling studies (e.g., GLP toxicology and scale up activities).
γ-分泌酶（GS）是治疗阿尔茨海默病潜在的关键靶点。虽然抑制GS会导致严重的副作用，但其调节具有提供安全治疗的巨大潜力。在此，我们报告了一种强效且选择性的γ-分泌酶调节剂（GSM）（）-（RO7185876）的发现，它属于新型化学类别，即三唑并氮杂卓类。该化合物在体外和体内均展现出优异的药物代谢动力学特性。此外，基于其在药效学小鼠模型中的体内疗效以及在两个物种中进行的剂量范围探索（DRF）毒理学研究结果，该化合物被选中进入人体支持性研究（例如，GLP毒理学和放大规模活动）。
