Discovery of Umibecestat (CNP520): A Potent, Selective, and Efficacious β-Secretase (BACE1) Inhibitor for the Prevention of Alzheimer’s Disease

Abstract

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.

Deciphering the Molecular Mechanism of Inhibition of β‐Secretase (BACE1) Activity by a 2‐Amino‐imidazol‐4‐one Derivative

“…The hydrogen bond analysis was performed for the central member of the conformational cluster having the highest conformations of the BACE1-L5 complex. L5 displayed three hydrogen bonds with aspartic dyad residues, i. e., Asp32 (0.18 nm, 0.25 nm) and Asp228 (0.20 nm) [Figure 6], which is consistent with the recent studies [29,44] that highlight hydrogen bond interactions of CNP520 and NB-360 with an aspartic dyad of BACE1 in the crystal structures of BACE1-CNP520 (PDB ID: 6EQM) and BACE1-NB-360 (PDB ID: 7BIQ). The hydrogen bond distance between BACE1 residues and L5 remains consistent during simulation (Figure 6, b-d), which depicts the structural stability of the BACE1-L5 complex.…”

“…The lead optimization identified compound 20 (AM‐6494, Figure S1) with a P3 propargyloxy group that displayed robust CSF (cerebral spinal fluid) Aβ 40 reduction in monkeys after injecting a single 10 mg/kg oral dose. Machauer et al [29] . discovered a potent, selective, and efficient BACE1 inhibitor, Umibecestat (CNP520, Figure S1), for the treatment of AD and highlighted that CNP520 significantly reduced Aβ levels in mice and rats without any side effects.…”

“…The lead optimization identified compound 20 (AM-6494, Figure S1) with a P3 propargyloxy group that displayed robust CSF (cerebral spinal fluid) Aβ 40 reduction in monkeys after injecting a single 10 mg/kg oral dose. Machauer et al [29] discovered a potent, selective, and efficient BACE1 inhibitor, Umibecestat (CNP520, Figure S1), for the treatment of AD and highlighted that CNP520 significantly reduced Aβ levels in mice and rats without any side effects. Nakahara et al [30] developed a series of novel 1-amino-3,4-dihydro-2,6-naphthyridine BACE1 inhibitors and identified orally efficacious compound 11 (Figure S1) by lead optimization that displayed robust and sustained Aβ reduction in the dog.…”

Amyloid Precursor Protein: A Regulatory Hub in Alzheimer's Disease

“…The bulk of initial BACE1 inhibitors were problematic due to low bioavailability and poor penetration across the blood–brain barrier. Second-generation BACE1 inhibitors (verubecestat [ 177 ], lanabecestat [ 178 ], atabecestat [ 179 ], LY3202626 [ 180 ], umibecestat [ 181 ]and elenbecestat [ 182 ]) were developed to be more lipophilic, and several have entered late-stage clinical trials but failed to show any cognitive or functional benefit in individuals with early AD or mild-to-moderate AD. These inhibitors decrease plasma and CSF Aβ levels and brain plaques but do not demonstrate clinical benefits.…”

Fe(OTf)3-catalyzed annulation of α,β-unsaturated ketoxime acetates with enaminones for the synthesis of functionalized 2,4-diarylpyridines

“…Pyridine skeletons are widely found in various natural products and synthetic biological molecules, which typically exhibit a broad spectrum of biological activities. These include anticancer activities, 1 Alzheimer's disease prevention, 2 treatment of asthma or hereditary angioedema, 3 cholesterol 24-hydroxylase inhibition, 4 and inhibition of cyclin-dependent kinase 5. 5 Consequently, various methods have been developed to synthesize pyridines.…”