Cathepsin D inhibitor

Plasmepsin II. The malarial aspartyl protease plasmepsin II has a significant homology (35%) to cathepsin D. Correspondingly, the very same approach as for the cathepsin D inhibitors (see above) was followed. The best inhibitors have Ki values of 2-10nM, a molecular weight <650, moderate selectivity vs. cathepsin D, the most closely related human protease, log P values <4.6, and no apparent binding to human serum albumin, for example, compound 36 Ki plasmepsin II = 2.0nM, Ki cathepsin D = 9.8nM Fig. 16.5) [111]. 

C. E. Lee, E. K. Kick, J. A. Ellman, General Solid-Phase Synthesis Approach to Prepare Mechanism-Based Aspartyl Protease Inhibitor Libraries. Identification of Potent Cathepsin D Inhibitors. J. Am. Chem. Soc 1998, 120, 9735-9747. 

Scheme 2.59 Cathepsin D inhibitors prepared using solid-supported reagent technology.

Figure 5.31 Structure of cathepsin D inhibitors 5.16-5.17 from libraries L4, L5, and L6.

Figure I. Chemical structures of representative ligands investigated A) biotin, B) 2-(4 -hydroxyazobenzene) benzoic acid (HABA), C) charged (X=CH2) and neutral (X=NH2 ) carboxylate MMP inhibitors, D) TtBO scaffold, E) sustiva, and F) hydroxyethylamine scaffold. The biotin derivatives," MMP inhibitors, TIBO analogs, and cathepsin D inhibitors derived from structures A), C), D), and F), respectively, have been published elsewhere.

Novel cathepsin D inhibitors block the formation of hyperphosphorylated tau fragments in hippocampus. Journal of Neurochemistry, 74, 1469-1477. 

Inhibitors for proteases plasmepsin I and II of the malaria parasite Plasmodium falciparum, with a good plasmepsin/human protease cathepsin D selectivity, have been identified via library construction involving rapid microwave-accelerated Suzuki reactions [57]. The phenyl ring of the biphenyl unit in the lead compound M-((lS)-l- [((lS,2S)-3- [(lS)-2-amino-l-(4-phenyl-benzyl)-2-oxoethyl]amino -2-hydroxy-l-phenoxypropyl)amino]carbonyl -2-methylpropyl)pyridine-2-carboxamide has been altered by performing Suzuki reactions on N-((lS)-l- [((lS,2S)-3- [(lS)-2-amino-l-(4-bromobenzyl)-2-oxoethyl]amino -2-hydroxy-l-phenoxypropyl)amino]carbonyl -2-methyl-propyl)pyridine-2-carboxamide (Scheme 37). In particular, a 2-benzofuryl moiety proved to be interesting since a Ki value of 13 nM for plasmepsin I and... 

Cathepsin D. The design of inhibitors of the aspartyl protease cathepsin D started from a virtual library of peptide analogs that contained the typical hydroxyethylamine isoster for the cleavable peptide bond. As the availability of starting materials would have generated a library of about 1 billion compounds, virtual screening was applied to reduce this multitude of candidate structures to a reasonable number. The backbone of a peptide... 

Poly(L-lysine) has also been suggested as a carrier for pepstatin, a specific inhibitor of the lysosomal proteinase cathepsin D, responsible for causing muscle-wasting diseases, such as muscular dystrophy [257],... 

Libraries of hundreds to thousands of spatially separate inhibitors have been prepared and screened to identify small molecule inhibitors of the human protease cathepsin D and the essential malarial proteases, plasmepsins I and II. The best inhibitors do not incorporate any amino adds and possess high affinity (Kj<5 nM).1241 Furthermore, these lead compounds were optimized by combinatorial methods for good physicochemical properties and minimal binding to human serum albumin. The optimized inhibitors effectively block cathepsin D-mediated proteolysis in human hippocampyl slices and are currently being used to evaluate the therapeutic potential of cathepsin D inhibition in the treatment of Alzheimer s disease. Additionally, the plasmepsin inhibitors serve as promising leads for the treatment of malaria. 

Wu et al. (1998) noted that doxombicin-induced apoptosis in lymphoid cells was blocked by pepstatin A, which is an inhibitor of cathepsin D. These investigators also observed that cathepsin D was induced through p53 DNA-binding sites at the cathepsin D promoter. Moreover, they have foimd that, compared to fibroblasts from wild-type mice, cathepsin D-/- fibroblasts from gene knock-out mice exhibited increased resistance to death caused by doxombicin. Also, in semm-deprived rat PC 12 cells undergoing apoptosis, the amoimt of cathepsin B has been observed to decline, while the level of cathepsin D increased (Shibata et al, 1998), and, in our laboratory (Kagedal et al, 2001), the same phenomenon was recently seen in human fibroblasts exposed to naphthazarin. 

The cytosolic targets of cathepsin D have not been ascertained. However, since we found that inhibition of cathepsin D prevented both release of cytochrome c and activation of caspase-3-like caspases, we suggest that cathepsin D exerts its effect upstream of both the release of cytochrome c from mitochondria and the onset of the caspase cascade. Cathepsin B seems to be of minor importance in this system, because we observed that the activity of cathepsin B decreased and the cathepsin B inhibitor CA074-Me had no influence on the rate of apoptosis (Kagedal et al 2001). 

Potent inhibitor of add proteases, including pepsin, renin and cathepsin D and many microbial aspartic proteases... 

Figure 6. An example of inter-family target hopping between human and viral aspartyl proteases. The aspartyl protease active site is located at a homodimer interface in HIV and within a single domain in Cathepsin D, so sequence and structure alignments between these proteins cannot be constructed. By using an approach independent of sequence or structure homology to directly align the sites, SiteSorter finds that the HIV protease and Cathepsin D substrate sites are highly similar (identical chemical groups within 1 A are colored dark blue). It has been verified experimentally that Cathepsin D is susceptible to inhibition by HIV-protease inhibitors. ...

S. K., Oh, H.-J., Yamashita, D. S., Veber, D. F. and Abdel-Meguid, S. S. (1998). Use of papain as a model for the structure-based design of cathepsin K inhibitors crystal structures of two papain-inhibitor complexes demonstrate binding to S/-subsites. /. Med. Chem. 41, 4567-4576. 

D. F. (1998). Stmcture-based design of cathepsin K inhibitors containing a benzyloxy-substituted benzoyl peptidomimetic. /. Med. Chem. 41,3923-3927. 

S. Leger, F. Masse, M.E. McGrath, D.J. McKay, M.D. Percival, D. Riendeau, S.B. Rodan, M. Therien, V.L. Truong, G. Wesolowski, R. Zambonia, W.C. Black, Identification of a potent and selective non-basic cathepsin K inhibitor, Bioorg. Med. Chem. Lett. 16 (2006) 1985-1989. 

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