After identification of lead compound 6, 5-amino-1,4-oxazine BACE1 inhibitors were optimized in order to improve potency, brain penetration, and metabolic stability. Insertion of a methyl and a trifluoromethyl group at the 6-position of the 5-amino-1,4-oxazine led to 8 (NB-360), an inhibitor with a pK_a of 7.1, a very low P-glycoprotein efflux ratio, and excellent pharmacological profile, enabling high central nervous system penetration and exposure. Fur color changes observed with NB-360 in efficacy studies in preclinical animal models triggered further optimization of the series. Herein, we describe the steps leading to the discovery of 3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid [6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide 15 (CNP520, umibecestat), an inhibitor with superior BACE1/BACE2 selectivity and pharmacokinetics. CNP520 reduced significantly Aβ levels in mice and rats in acute and chronic treatment regimens without any side effects and thus qualified for Alzheimer’s disease prevention studies in the clinic.

中文翻译：

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发现 Umibecestat (CNP520)：一种强效、选择性和有效的 β-分泌酶 (BACE1) 抑制剂，用于预防阿尔茨海默病

在确定先导化合物6 后，对 5-氨基-1,4-恶嗪 BACE1 抑制剂进行了优化，以提高效力、大脑渗透和代谢稳定性。在 5-amino-1,4-oxazine 的 6-位插入甲基和三氟甲基导致8 ( NB-360 )，一种 ap K _a为 7.1的抑制剂，具有非常低的 P-糖蛋白流出率，以及出色的药理特性，可实现高中枢神经系统渗透和暴露。使用NB-360观察到的毛皮颜色变化在临床前动物模型的功效研究中，引发了对该系列的进一步优化。在此，我们描述了导致发现 3-氯-5-三氟甲基-吡啶-2-羧酸 [6-((3 R ,6 R )-5-氨基-3,6-二甲基-6-三氟甲基-3,6-dihydro-2 H -[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide 15 ( CNP520 , umibecestat )，一种具有优异 BACE1/BACE2 选择性和药代动力学的抑制剂. CNP520在急性和慢性治疗方案中显着降低小鼠和大鼠的 Aβ 水平，没有任何副作用，因此符合临床阿尔茨海默病预防研究的要求。