8-Tetrahydropyran-2-yl Chromans: Highly Selective Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitors

Abstract

A series of 2,3,4,4a,10,10a-hexahydropyrano[3,2-b]chromene analogs was developed that demonstrated high selectivity (>2000-fold) for BACE1 vs Cathepsin D (CatD). Three different Asp-binding moieties were examined: spirocyclic acyl guanidines, aminooxazolines, and aminothiazolines in order to modulate potency, selectivity, efflux, and permeability. Guided by structure based design, changes to P2' and P3 moieties were explored. A conformationally restricted P2' methyl group provided inhibitors with excellent cell potency (37-137 nM) and selectivity (435 to >2000-fold) for BACE1 vs CatD. These efforts lead to compound 59, which demonstrated a 69% reduction in rat CSF Aβ1-40 at 60 mg/kg (PO).

Toward β-Secretase-1 Inhibitors with Improved Isoform Selectivity

“…We found that a hydrogen bond acceptor in proximity of the S3 subpocket in combination with a small substituent at the cyclohexyl A-ring occupying the volume neighboring the flap region led to optimal BACE1 selectivity. It is conceivable that these “selectivity hotspots” can be exploited in a similar manner using known BACE inhibitors such as aminohydantoins or other scaffolds as structural starting points. ,, A number of new inhibitors were investigated starting from a central di-spiro scaffold and an aminooxazoline headgroup. We replaced the CH 2 element of this head group by CD 2 , initially with the aim to reduce metabolic vulnerability.…”

The utilization of spirocyclic scaffolds in novel drug discovery

“…BACE1 (β-secretase) is a prominent target in the quest for a disease-modifying therapeutic for Alzheimer's disease. Weakly basic aminoheterocycles (the amidine moiety) emerged as the preeminent motif for interaction with the two catalytic aspartate residues in BACE1 [8], and researchers at several organizations chose to deploy this pharmacophore as part of a spirocycle (1-3) [9][10][11]. Compound 3 is an analog of the clinical candidate verubecestat which lacks the spirocyclopropane feature.…”

Preparation and Synthetic Applications of Five-to-Seven-Membered Cyclic α-Diazo Monocarbonyl Compounds

“…The insertion into the O-H bond of alcohols is poorly studied. However, selected literature examples demonstrate that the reaction can be catalyzed by Lewis acids [ 63 , 64 ] as well as transition metal complexes [ 65 ]. The insertion into the O-H bond of allylic alcohols is of much interest, as it can be accompanied by a subsequent sigmatropic rearrangement.…”