The latest chapter in Amgen’s pursuit of new Alzheimer’s disease (AD) treatments includes a global collaboration focused on the β-site APP-cleaving enzyme-1 (BACE1) gene, a target first cloned by Amgen and now supported by human genetic validation. In 2012, deCODE Genetics - a subsidiary of Amgen - announced it had found a rare, protective mutation that involved the amyloid pathway. This was an exciting milestone towards validating the beta-amyloid hypothesis, but development of a clinically relevant therapeutic to treat AD remains an unmet medical need.<br/>This newly gained genetic insight coincided with our discovery of a new series of BACE1 inhibitors – the cyclopropyloxazines. Herein we describe the challenges that were overcome by our team to optimize the properties of these molecules combined with the necessity to develop novel chemistry as these complex structures posed significant synthetic challenges. For example, a highly diastereoselective nucleophilic addition reaction led to the formation of three contiguous stereocenters and enabled the synthesis of the pre-clinical candidate AMG 978.<br/>In addition, a preview of the discovery of related cyclopropylthiazine BACE1 inhibitors will be given and the impact of a single-atom change from oxygen to sulfur on the chemical synthesis will be discussed.

Fueling the Alzheimer's BACE1 race with genetic insights and cyclopropyloxazine BACE1 inhibitors

254th National Meeting (2017)

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