An Orally Available BACE1 Inhibitor That Affords Robust CNS Aβ Reduction without Cardiovascular Liabilities

Abstract

BACE1 inhibition to prevent Aβ peptide formation is considered to be a potential route to a diseasemodifying treatment for Alzheimer's disease. Previous efforts in our laboratory using a combined structure-and propertybased approach have resulted in the identification of aminooxazoline xanthenes as potent BACE1 inhibitors. Herein, we report further optimization leading to the discovery of inhibitor 15 as an orally available and highly efficacious BACE1 inhibitor that robustly reduces CSF and brain Aβ levels in both rats and nonhuman primates. In addition, compound 15 exhibited low activity on the hERG ion channel and was well tolerated in an integrated cardiovascular safety model. KEYWORDS: β-site amyloid precursor protein cleaving enzyme 1 (BACE1), Alzheimer's disease (AD), Aβ, aminooxazoline, xanthene A lzheimer's disease (AD) is the most common neurodegenerative disorder and accounts for 50−80% of dementia cases identified each year. Current therapeutics for AD only provide temporary symptomatic relief and do not address the underlying neuropathology. A therapeutic treatment that directly modifies the progression of the disease remains one of the largest unmet medical needs in neurobiology.The most widely held hypothesis for the underlying pathogenesis of AD posits that aggregation of β-amyloid peptides (Aβ) and deposition into amyloid plaques in the neural parenchyma play an essential role. Aβ is produced by sequential endoproteolytic cleavage of amyloid precursor protein (APP) by the aspartyl protease β-site APP cleaving enzyme-1 (BACE1) and γ-secretase.

BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

“…Other classes of amino azines inhibitors are compounds containing the amino‐oxazoline and xanthene cores, which showed a remarkable inhibition potency against BACE1. However, these compounds were found to exhibit high P‐gp efflux ratio . Functionalization of the xanthene core led to compound 20 possessing a 3‐aza‐2‐fluoroxanthene moiety reported by Cheng et al Inhibitor 20 is a highly effective BACE1 inhibitor that significantly reduced the brain and CSF Aβ levels in both rats and nonhuman species .…”

“…Other hydrogen bonds formed between the oxygen of the dihydropyran and Tyr198. The pyridyl nitrogen formed an extra hydrogen bond with Ser229 (Figure ) …”

“…72 Functionalization of the xanthene core led to compound 20 possessing a 3-aza-2-fluoroxanthene moiety reported by Cheng et al Inhibitor 20 is a highly effective BACE1 inhibitor that significantly reduced the brain and CSF Aβ levels in both rats and nonhuman species. 72 X-ray costructural studies of inhibitor 20 bound to BACE1 showed that the 3-azaxanthene core formed strong hydrogen bonding interactions with Trp76. Other hydrogen bonds formed between the oxygen of the dihydropyran and Tyr198.…”

“…The pyridyl nitrogen formed an extra hydrogen bond with Ser229 ( Figure 8). 72 Another expansion of these amino azines scaffolds was developed by including the substituted aminoxazines, which showed potent activity against BACE1. For example, compound 21 possesses an IC 50 of 12 nM and cellular IC 50 of 2 nM.…”

Computer-Aided Drug Design of β-Secretase, γ-Secretase and Anti-Tau Inhibitors for the Discovery of Novel Alzheimer’s Therapeutics

“…Sequence alignment analysis showed that the amino acid sequences of human BACE1 and BACE2 gene coding regions are 45% identical and 75% homologous [22]. Numerus crystal structures of BACE1 have been resolved with and without inhibitor in its active site [23][24][25][26][27][28][29][30][31][32]. BACE1 contains an N-terminal protease domain, a connecting strand, a transmembrane region, and a cytosolic domain [23].…”