Plasmepsins

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... 

Interestingly plasmepsin inhibitors with a good activity (low nM) were obtained with no measurable affinity to the human protease enzyme. 

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]. 

Haque TS, Skillman AG, Lee CE, Habashita H, Gluzman lY, Ewing TJA, Goldberg DE, Kuntz ID, Ellman JA. Potent, low-molecnlar-weight non-peptide inhibitors of malarial aspartyl protease plasmepsin II. J Med Chem 1999 42 1428-40. 

Scheme 6.22 Decoration ofthe PT subunit in plasmepsin I inhibitors.

Scheme 6.23 Synthesis of plasmepsin I and II inhibitors with elongated Pl/PT side chains.

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. 

Plasmepsin II inhibitor, Ki 2 nM from structure-based library design... 

The DOCK combinatorial docking implementation [275] was also applied for the design of novel enzyme inhibitors [276, 277]. In one of these prospective examples, Haque et al. reported potent low-nanomolar plasmepsin II aspartyl-protease inhibitors [278] from a set of several focused libraries with a best Ki value of 2 nM (cf Figure 4.5f). 

The Pd-catalyzed carbonylation of o-vinylaryl bromides using Mo(CO)6 as CO source with microwave irradiation gave indanone 338 and 3-acylaminoindanone 340, which are key intermediates for the synthesis of inhibitors of human immunodeficiency virus type 1 (HIV-1) protease and Plasmepsin I and II (Scheme 46). These polycyclic compounds were obtained in less than 30 min in high yields. The results clearly indicate the power and advantage of this protocol, especially for the combinatorial parallel synthesis of a library of compounds. 

Plasmepsin I and II subsequently cleave the resulting fragments at secondary sites. It should be noted that the enzymes have alternate... 

Scheme 2.8 Synthesis of plasmepsin inhibitors by microwave-assisted Suzuki couplings.

Scheme 2.9 Library synthesis of plasmepsin inhibitors with diverse PI side chains from arylboronic acid reagents.

Noteberg, D., Hamelink, E., Hulten, J., Wahlgren, M., Vrang, L. etal, Design and synthesis of Plasmepsin I and Plasmepsin Ii inhibitors with activity in Plasmodium Falciparum-infected cultured human erythrocytes,... 

Scheme 2 Microwave-assisted synthesis of highly potent hydroxyethylamine plasmepsin inhibitors...

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