Macrocyclic prolinyl acyl guanidines as inhibitors of β-secretase (BACE)

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

“…It has also been found that, adding a pyrrolidine moiety to guanidine‐containing compounds, such as compound 13 , which is substituted at position 4 with N‐acyl pyrrolidine group, resulted in the development of one of the most potent compounds compared with similar derivatives in the same series with BACE1 K i value of 0.21 μM. Molecular modeling studies of this compound revealed a unique U‐shaped conformation that directs the aryl group toward S2 subpocket of BACE1 …”

“…In the same series, compound 14 was the most active, with BACE1 K i value of 0.0032 μM and low P‐gp efflux ratio of 2.3. Interestingly, the rigidification strategy led to macrocyclic derivatives that exhibited a great selectivity over other acyclic derivatives in which compound 14 showed 700‐fold selectivity over CatD …”

“…42,67 It has also been found that, adding a pyrrolidine moiety to shaped conformation that directs the aryl group toward S2 subpocket of BACE1. 68 Furthermore, structure-activity relationship (SAR) studies of these inhibitors revealed that the addition of an ether linkage on the aryl group was highly tolerated, which encouraged researchers to pursue macrocyclization.…”

“…Interestingly, the rigidification strategy led to macrocyclic derivatives that exhibited a great selectivity over other acyclic derivatives in which compound 14 showed 700-fold selectivity over CatD. 68 It is worth to mention that one of the highly effective compounds containing the guanidine scaffold is compound 15: MK-8931 (verubecestat/Merck), which is the first BACE1 inhibitor to reach phase III clinical trials. This compound has remarkable physiochemical properties, including improved oral bioavailability, cellular penetration, and brain permeability.…”

Tandem Aryne‐Capture/Sigmatropic Rearrangement as a Metal‐Free Entry to Functionalized N‐Aryl Pyrrolidines

“…[1,2] Within this diverse class of molecules, the 2acylpyrrolidine motif is well-knowna sacomponent of proteins (in the amino acid proline) and prolineanaloguesoccur as subunits of many biologically actives ynthetic substances, including pharmacologically relevantm olecules and functional probess uch as ion sensors (Figure 1). [3] Though the N-aryl and N-naphthyl proline is presenti nm any such drug-like substances, [4] methods to access these structuresa re limited, with the Ullmann-Goldberg reaction [5] being mosto ften used to prepare the molecules (Scheme 1a), ap rocess which usually necessitates elevated temperatures and high catalyst loading. [6] Due to this scarcity of synthetic methods, there has been recent interest in the development of novel methods to deliver N-aryl pyrrolidines.…”