Structure- and Ligand-Based Modeling of Beta-Secretase 1 (BACE1) Inhibitors

There exists a broad consensus among the Alzheimer's disease research community that the key to successful treatment lies in the specific inhibition of beta-amyloid converting enzyme 1 (BACE1). A series of transition-state analogues of BACE1 inhibitors containing fused aryl or biaryl moieties were designed computationally to probe the S2 pocket of BACE1, synthesized, and tested for inhibitory activity. The structure-activity relationship of these inhibitors will be discussed. It has been shown that unlike the bi-aryl, the fused-ring moiety is successfully accommodated in the binding site resulting in ligands with excellent inhibitory activity. When mouse neuroblastoma cells (N2a) are treated with active BACE1 inhibitors 5b and 5c, a reduction in Aβ40 production, c.a. 65% and 35% respectively, compared to the control, was observed. To get additional insights into BACE1 ligand design, we have developed a quantitative structure activity relationship (QSAR) for ‘non-peptidomimetic' BACE1 inhibitors using comparative molecular field analysis (CoMFA). The reported 3D-QSAR model is statistically significant thereby demonstrating a sound SAR for inhibitors that bind to the catalytic site of BACE1. For CoMFA analysis, the statistical parameters are: R2NV = 0.98, R2CV = 0.64, R2LOO = 0.67, SEE = 0.154, F = 287.219 and R2PRED = 0.74. This model should be useful for the identification, design and development of potential BACE1 inhibitors

Low Molecular Weight Amidoximes that Act as Potent Inhibitors of Lysine-Specific Demethylase 1

The recently discovered enzyme lysine-specific demethylase 1 (LSD1) plays an important role in the epigenetic control of gene expression, and aberrant gene silencing secondary to LSD1 dysregulation is thought to contribute to the development of cancer. We reported that (bis)­guanidines, (bis)­biguanides, and their urea- and thiourea isosteres are potent inhibitors of LSD1 and induce the re-expression of aberrantly silenced tumor suppressor genes in tumor cells in vitro. We now report a series of small molecule amidoximes that are moderate inhibitors of recombinant LSD1 but that produce dramatic changes in methylation at the histone 3 lysine 4 (H3K4) chromatin mark, a specific target of LSD1, in Calu-6 lung carcinoma cells. In addition, these analogues increase cellular levels of secreted frizzle-related protein (SFRP) 2, H-cadherin (HCAD), and the transcription factor GATA4. These compounds represent leads for an important new series of drug-like epigenetic modulators with the potential for use as antitumor agents

Mechanism of Inactivation of GABA Aminotransferase by (<i>E</i>)- and (<i>Z</i>)‑(1<i>S</i>,3<i>S</i>)‑3-Amino-4-fluoromethylenyl-1-cyclopentanoic Acid

When γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the mammalian central nervous system, falls below a threshold level, seizures occur. One approach to raise GABA concentrations is to inhibit GABA aminotransferase (GABA-AT), a pyridoxal 5′-phosphate-dependent enzyme that degrades GABA. We have previously developed (1<i>S</i>,3<i>S</i>)-3-amino-4-difluoromethylene-1-cyclopentanoic acid (CPP-115), which is 186 times more efficient in inactivating GABA-AT than vigabatrin, the only FDA-approved inactivator of GABA-AT. We also developed (<i>E</i>)- and (<i>Z</i>)-(1<i>S</i>,3<i>S</i>)-3-amino-4-fluoromethylenyl-1-cyclopentanoic acid (<b>1</b> and <b>2</b>, respectively), monofluorinated analogs of CPP-115, which are comparable to vigabatrin in inactivating GABA-AT. Here, we report the mechanism of inactivation of GABA-AT by <b>1</b> and <b>2</b>. Both produce a metabolite that induces disruption of the Glu270–Arg445 salt bridge to accommodate interaction between the metabolite formyl group and Arg445. This is the second time that Arg445 has interacted with a ligand and is involved in GABA-AT inactivation, thereby confirming the importance of Arg445 in future inactivator design