BACE inhibitor

The identification of a small, brain penetrant BACE-1 inhibitor has been sought after for nearly a decade. There are patents and publications of brain penetrant BACE-1 inhibitors, and for a recent review of such compounds, the interested reader is referred to the report by Hills and Vacca.1241... 

Figure 9.10 PV amine substituents were selected prospectively for a BACE-1 inhibitor scaffold. Note the dashed circle (above) and dashed line (below) indicating the point of attachment. The real (top) and virtual (bottom) chemistries are depicted beneath the scaffold.

Figure 9.12). In addition, our arbitrary cut-off for the energy score may have missed some interesting inhibitors, e.g. the ethyl- and isobutylamines which are labeled as Below cutoff in Figure 9.12. However, the score versus activity trend is clear, including a true negative control, the tert-butylamine reagent, which was predicted (and subsequently observed) to yield an inhibitor with very low BACE-1 activity. In addition to demonstrating the utility of an in situ virtual reagent selection, this study served to validate the hypothesis that the BACE-1 SF pocket is large, open and promiscuous, as a variety of reagents led to potent BACE-1 inhibitors.

Hills I.D., Vacca J.P., Progress toward a practical BACE-1 inhibitor. Cum Opin. Drug Discov. Dev. 2007, 10, 383-391. 

A high-throughput screening (HTS) campaign to identify S-secretase (BACE-1) inhibitors provided compound 1 (Fig. 1) as a promising new hit which was quickly optimized to compound 2 with the aid of an Ugi MCR [10]. Although compound... 

Moitessier, N., Therrien, E., Hanessian, S. A method for induced-fit docking, scoring, and ranking of flexible ligands. Application to peptidic and pseudopeptidic beta-secretase (BACE 1) inhibitors. J. Med. Chem. 2006, 49(20), 5885. 

Hydroxyethylamine (HEA) BACE-1 inhibitors 2, 2-Dioxo-isothiochromanes Chroman-HEA derivatives Hydroxyethylene-based BACE-1 Inhibitors Iminopyrimidinone derivatives... 

Other novel BACE-1 inhibitors with a hydroxyethylene central core have been developed [401], as well as spirocyclic BACE1 inhibitors [402], phenylimino-2H-chromen-3-carboxamide derivatives [403], iminopyrimidinone derivatives [404], or sulfonamide chal-cones [405],... 

Ng RA, Sun M, Bowers S, Horn RK, Probst GD, John V et al (2013) Design and synthesis ofhydroxyethylamine (HEA) BACE-1 inhibitors Prime side chromane-containing inhibitors. Bioorg Med Chem Lett 23 4674-4679... 

Sandgren V, Back M, Kvarnstrom I, Dahlgren A (2013) Design and synthesis of hydroxyethylene-based BACE-1 inhibitors incorporating extended PI substituents. Open Med Chem J 7 1-15... 

Brodney MA, Barreiro G, Ogilvie K, Hajos-Korcsok E, Murray J, Vajdos F et al (2012) Spirocyclic sulfamides as fysecretase 1 (BACE-1) inhibitors for the treatment of Alzheimer s disease Utilization of structure based drug design, WaterMap, and CNS penetration studies to identify centrally efficacious inhibitors. J Med Chem 55 9224-9239... 

Combining NMR and X-ray Crystallography in Fragment-Based Drug Discovery Discovery of Highly Potent and Selective BACE-1 Inhibitors... 

BACE-1 is a membrane-anchored aspartic acid protease that is localized to the acidic compartments of endosomes and lysosomes in the CNS and has an optimal enzymatic activity at around pH 5. As a consequence, a BACE-1 inhibitor needs to be able to cross the blood-brain barrier and to have a significant non-protein bound fraction in order to reach the active site of the enzyme. This makes traditional aspartic protease inhibitors, which typically are large and peptidic, unsuitable as BACE-1 inhibitors. Moreover, the BACE-1 active site is extended, shallow and hydrophilic (Fig. 2) [99]. Therefore, the development of potent, selective, orally active, and brain penetrant low MW compounds has been a big challenge for the pharmaceutical industry [101, 102],... 

Despite this structural knowledge it still turned out to be challenging to significantly improve the potency of the iminohydantoin series with respect to cellular potency and PK properties. However, by use of structure-assisted SAR development the team was ultimately able to develop BACE-1 inhibitors with high affinity,... 

Stachel SJ (2009) Progress toward the development of a viable BACE-1 inhibitor. Drug Dev Res 70 101-110... 

Yang W, Fucini RV, Fahr BT, Randal M, Lind KE, Lam MB, Lu W, Lu Y, Cary DR, Romanowski MJ, Colussi D, Pietrak B, Allison TJ, Munshi SK, Penny DM, Pham P, Sun J, Thomas AE, Wilkinson JM, Jacobs JW, McDowell RS, Ballinger MD (2009) Fragment-based discovery of nonpeptidic BACE-1 inhibitors using tethering. Biochemistry 48 ... 

Huang, W., Yu, H., Sheng, R., Li, J., and Hu, Y. (2008) Identification of pharmacophore model, synthesis and biological evaluation of N-phenyl-l-arylamide and N-phenylbenzenesulfonamide derivatives as BACE 1 inhibitors. Bioorganic e[ Medicinal Chemistry, 16, 10190-10197. 

Figure 9.39 Effects of replacing an amide with a trifluoroethylamine isostere on target activity and P-gp efflux as determined in a cellular transport assay. References 6 and 7 are from the original publication. (Reprinted with permission from Moore, K.P., et al. Strategies toward improving the brain penetration of macrocyclic tertiary carbinamine BACE-1 inhibitors. Bioorg. Med. Chem. Lett. 2007 17, 5831-5835, copyright 2007, Elsevier).

Moore, K.P., et al. Strategies toward improving the brain penetration of macrocyclic tertiary carbinamine BACE-1 inhibitors. Bioorg. Med. Chem. Lett. 2007, 17, 5831-5835. 

Compounds featuring this typical functionalized cyclopentane unit are the platelet aggregation inhibitor compound (1) of AstraZeneca, the HCV NS3 NS4A protease inhibitor (2) claimed by Tibotec for the treatment of Hepatitis C, and a Neuraminidase (Sialidase) inhibitor (3) discovered by Biocryst for the treatment of influenza (Figure 4.6). Likewise, the widely used nucleoside analog reverse transcriptase inhibitor Abacavir (4), administered against HIV, produced by GlaxoSmithKline, as well as Medivir s beta-secretase 1 (BACE 1) inhibitor (5) for the treatment of Alzheimer s dementia can be probably derived from this hydroformylation protocol. 

Industrially, this reaction is very useful, and, in 2007, Merck research labs reported the synthesis of macrocyclic tertiary carbinamine BACE-1 inhibitors - BACE-1 inhibition is widely regarded to be one of the promising therapeutic approaches for the treatment of Alzheimer s disease - where the Negishi reaction was used as a key step (Scheme 1.56) [179]. 

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