Optimization of 1,4-Oxazine β-Secretase 1 (BACE1) Inhibitors Toward a Clinical Candidate

Abstract

In previous studies, the introduction of electron withdrawing groups to 1,4-oxazine BACE1 inhibitors reduced the p K of the amidine group, resulting in compound 2 that showed excellent in vivo efficacy, lowering Aβ levels in brain and CSF. However, a suboptimal cardiovascular safety margin, based on QTc prolongation, prevented further progression. Further optimization resulted in the replacement of the 2-fluoro substituent by a CF-group, which reduced hERG inhibition. This has led to compound 3, with an improved cardiovascular safety margin and sufficiently safe in GLP toxicity studies to progress into clinical trials.

JNJ-67569762, A 2-Aminotetrahydropyridine-Based Selective BACE1 Inhibitor Targeting the S3 Pocket: From Discovery to Clinical Candidate

“…As shown in Chart , all compounds that entered phase III clinical studies share this pharmacophore, including elenbecestat 1 (Eisai/Biogen), verubecestat 2 (Merck), umibecestat 3 (Novartis/Amgen), lanabecestat 4 (AstraZeneca/Lilly), and atabecestat 5 (Janssen/Shionogi) . The 1,4-oxazine clinical candidate 6 that we reported recently equally shares this general pharmacophore . Besides CNS penetration and cathepsin D-related toxicity, many other challenges were overcome in the development of these compounds, such as avoiding cardiovascular toxicity and phospholipidosis, which have both been associated to the basicity of the amidine, and liver toxicity, which has been associated with chemotypes like the unsaturated 1,3-thiazine in 5 .…”

“…BACE1 enzymatic activity was assessed by a FRET (fluorescence resonance energy transfer) assay as described previously . BACE2 enzymatic activity was assessed by a FRET assay using an APP (amyloid precursor protein)-derived 13-amino acid peptide that contains the “Swedish” Lys-Met/Asn-Leu mutation of the APP β-secretase cleavage site as a substrate (Bachem catalogue no.…”

Evaluation of a Series of β-Secretase 1 Inhibitors Containing Novel Heteroaryl-Fused-Piperazine Amidine Warheads

“…This optimization focused on achieving a p K a within the range of 6.5–7.5. The evolution of the series ultimately culminated with the identification of 4 (Figure ), a recently disclosed clinical candidate …”

“…The morpholine series, exemplified by JNJ-50138803 (4) (Figure 1), was also supported by in silico work, and its optimization has been described. 11,12 The initial prototypes displayed high pK a values (9 < pK a < 9.6) and a strong Pgp-mediated efflux liability. 11 To attenuate the issues attributed to the elevated pK a , the amidine warhead was carefully modified with fluorine containing electron withdrawing substituents at position C-2 of the morpholine ring.…”

“…The evolution of the series ultimately culminated with the identification of 4 (Figure 1), a recently disclosed clinical candidate. 12 Besides the exploration of the morpholine series, here we described a parallel effort using bioisosteric replacements of the amide in the aminopiperazinone warhead (3). We focused on replacing this amide functional group by nitrogen-containing fused five membered heteroaromatic rings, where a bridge head nitrogen was maintained.…”