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

Abstract

Despite several years of research, only a handful of β-secretase (BACE) 1 inhibitors have entered clinical trials as potential therapeutics against Alzheimer's disease. The intrinsic basic nature of low molecular weight, amidine-containing BACE 1 inhibitors makes them far from optimal as central nervous system drugs. Herein we present a set of novel heteroaryl-fused piperazine amidine inhibitors designed to lower the basicity of the key, enzyme binding, amidine functionality. This study resulted in the identification of highly potent (IC 50 ≤ 10 nM), permeable lead compounds with a reduced propensity to suffer from P-glycoprotein-mediated efflux.

Syntheses and Applications of 1,2,3-Triazole-Fused Pyrazines and Pyridazines

“…Primary Applications: Benzo-fused or saturated piperazine-containing analogs are common. Notable reports include identification of a 1,2,3-triazole-fused quinoxalinone as inducing Rgg2/3-related gene expression in the human pathogen Streptococcus pyrogenes , as a potent DPP IV inhibitor [ 7 ], and as a BACE-1 inhibitor [ 6 ]. 1,2,3-Triazolo[4,5-c]pyridazines : The most common method is cyclization of the respective diaminopyridazine with nitrite [ 3 , 74 , 91 , 92 , 93 ].…”

“…Partially saturated 1,2,3-triazolo[1,5- a ]pyrazines have demonstrated BACE-1 inhibition, an enzyme implicated in the formation of amyloid beta in Alzheimer’s disease. Oehlrich and coworkers [ 6 ] identified one such candidate, ( R )- N -(3-(4-amino-6-methyl-6,7-dihydro-[1,2,3]triazolo[1,5- a ]pyrazin-6-yl)-4-fluorophenyl)-5-cyanopicolinamide, (Structure C, Figure 7 ). This demonstrated an inhibition of the BACE-1 enzyme of pIC 50 = 8.70.…”

“…We became interested in structures containing heterocyclic nuclei 2 , 4 , 6 , 8 and 10 following reports detailing potent mesenchymal–epithelial transition factor (c-Met) protein kinase inhibition, such as the current clinical candidate Savolitinib [ 1 ] ( Figure 2 , Structure A) and specifically those containing substructures 2 and 8 [ 1 , 2 ]. In addition to c-Met inhibition, structures containing these heterocyclic nuclei have shown GABA A allosteric modulating activity [ 3 ] ( Figure 2 , Structure B), have been incorporated into polymers for use in solar cells [ 4 , 5 ] ( Figure 2 , Structure C), and have demonstrated -secretase 1 (BACE-1) inhibition [ 6 ] ( Figure 2 , Structure D). Their piperazine derivatives have demonstrated potent PDP-IV inhibition [ 7 ].…”

Access to Triazolopiperidine Derivatives via Copper(I)‐Catalyzed [3+2] Cycloaddition/Alkenyl C−N Coupling Tandem Reactions

“…For example, [1,2,3]‐triazolo‐piperidine derivatives 1 – 4 , which have been identified as Hsp90 inhibitor, DPP‐4 inhibitor, BACE 1 inhibitor and antifungal agent respectively, and shown potent activities in the treatment of a variety of diseases (Figure 1). [2–5] …”

Cyclopentanone Derivative Attenuates Memory Impairment by Inhibiting Amyloid Plaques Formation in the 5xFAD Mice

“…In vivo experiments were carried out following Animals' Scientific Procedures Act (UK), 1986, and procedures were approved by the ethical committee of the Pharmacy Department, University of Peshawar (reference number 12/EC-17/Pharm). The crystal structure of the BACE1 enzyme was fetched from the protein data bank (PDB) available under PDB id: 6OD6 [52], resolution of 2 Å and R-value of 0.22 in UCSF Chimera and subsequently subjected to receptor preparatory phase [53]. First, associated co-crystallized ligands and water molecules not relevant for enzyme functionality were discarded and then the enzyme was saved in pdb format.…”