Alzheimer’s disease is a neurodegenerative disorder characterized by progressive memory loss ultimately leading to dementia. The abnormal accumulation of extracellular Ab in the brain in the form of soluble oligomers or insoluble plaques is one of the key hallmarks of this devastating disease. We previously reported on the fragment-based discovery of LY2811376, the first BACE1 inhibitor reported to demonstrate robust reduction of human CSF Aβ in a Phase I clinical trial. More recently, we reported on the discovery of LY2886721, a potent BACE1 inhibitor that was the first BACE1 inhibitor to reach Phase 2 clinical trials. This presentation will include the design and complex organic syntheses required to prepare several series of topologically complex aminothiazine BACE1 inhibitors as well as preclinical and clinical data from Lilly’s BACE1 inhibitor program.

Complex organic synthesis in drug discovery: Examples from Lilly’s BACE inhibitor program

254th National Meeting (2017)

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