Aspartyl proteases inhibitors

Example of Scheme C When Kf K, Aspartyl Protease Inhibitors... 

Figure 7. Potent aspartyl protease inhibitors synthesized from simple Grignard, amine, acid, sulfonyl chloride, and isocyanate building blocks.

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. 

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 discovery of yet other nonhydrolyzable amide bond isosteres has particularly impacted the design of protease inhibitors, and these include hydroxymethylene or FfCF OH)], 12 hydroxyethylene or T fCF OFQCFy and T fCFkCHiOH)], 13 and 14, respectively dihydroxyethylene or ( [ )], 15, hydroxyethylamine or 4 [CH(0H)CH2N], 16, dihydroxyethylene 17 and C2-symmetric hydroxymethylene 18. In the specific case of aspartyl protease inhibitor design (see below) such backbone modifications have been extremely effective, as they may represent transition state mimics or bioisosteres of the hypothetical tetrahedral intermediate (e.g., xF[C(OH)2NH] for this class of proteolytic enzymes. 

Additionally, 1,2-dihydroxyethylene dipeptide analogues without the C-terminal carboxylic acid have been used to obtain aspartyl proteases inhibitors.[641 These efforts include stereoselective alkylation of imines, one-pot reductive amination of epoxy ketones, ring opening of epoxides with sodium azide, diastereoselective dihydroxylation of allylic amines, and enzymatic resolution and stereocontrolled intramolecular amidation. 

Figure 5.29 Retrosynthesis of a biased targeted library aimed at aspartyl protease inhibitors.

Specker, E., Bottcher, J., Brass, S., Heine, A., Lilie, H., Schoop, A., Muller, G., Griebenow, N., Klebe, G. Unexpected novel binding mode of pyrrolidine-based aspartyl protease inhibitors design, synthesis and crystal structure in complex with HIV protease. Chem. Med. Chem. 2006, 1, 106-117. 

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