Cathepsin A inhibitors

The Discovery of Cathepsin A Inhibitors A Project-Adapted Fragment Approach Based on HTS Results... 

Ito, K., Nakama, H., Hayashi, Y., and lijima, K. (2005) Cathepsin A inhibitors containing disubstituted l-phenylalanines and pharmacuetical compositions containing the inhibitors. JP2005145839. 

Ruf, S., Sadowski, T., Buning, C, Schreuder, H. et al. (2012) Preparation of heteroarylaminopropionic acid derivatives for use as protease cathepsin A inhibitors. W02012101197. 

The last part exemplifies the above-mentioned methods and strategies in eight impressive success stories on lead structure discovery in many different areas, such as H3 antagonists, PAR-1 antagonists, inhaled K2-receptor agonists, and cathepsin A inhibitors, or in projects for neglected diseases, to mention a few. 

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]. 

When the target enzyme is difficult to obtain, related enzymes could be used to provide insights in the design of novel ligands. For example, papain was used to design a class of potent cathepsin K inhibitors [33] spanning both sides of the papain active site. However, fine-tuning these inhibitors to produce more potent ones required the use of the crystal structure of cathepsin K itself [34],... 

LaLonde JM, Zhao B, Smith WW, Janson CA, DesJarlais RL, Tomaszek TA, Carr TJ, Thompson SK, Oh HJ, Yamashita DS, Veber DF, Abdel-Meguid SS. 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. J Med Chem 1998 41 4567-4576. 

The synthesis of the /V-protected 7-methylazepine derivative 34 was achieved in 89% yield by a ring-closing metathesis reaction on 33 mediated by Grubbs I ruthenium catalyst. This azepine was an important precursor for the preparation, via epoxidation of the double bond, of a number of 7-methylazepanone derivatives for evaluation as cathepsin K inhibitors <06JMC1597>. 

A novel class of cathepsin B inhibitors has been developed with a 1,2,4-thiadiazole heterocycle as the thiol-trapping pharmacophore. The most potent inhibitor is compound 128 <2003BML5529>. 

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. 

Fig. 5.5 On-line HPLC bioactivity screening of a mixture of five flavonoids spiked with two cathepsin B inhibitors, E-64 and leupeptin using acetylcholinesterase as biological target. MS instrument Shimadzu LCMS-2010 single-stage quadrupole mass spectrometer, (a) TIC chromatogram of the mixture, scan range m/z 75-750 (b) mass chromatogram of AMC (m/z 176) (c) mass...

Figure 10. Binding site anaiysis of different species can uncover potentiai probiems with ani-mai modeis for a given target. The Cathepsin S inhibitor JNJ 10329670 (exact molecule not shown) has an activity of 34 nM in humans, but shows sub-micromolar activity in dog, monkey, and cattie, and oniy micromoiar activity in mice. These activity differences can be expiained by the fact that in the dog, monkey and bovine Cathepisin S pockets, only two of the residues are non-conserved, whiie four of the residues are non-consen/ed in mice.

Figure 17.3 Schematic representation of the design of the symmetric cathepsin K inhibitor diacylaminomethyl ketone (1,3-bis[[A/-[(phenylmethoxy)carbonyl]-L-leucyl]amino]-2-propanone), based on the crystal structures of papain bound to leupeptin (Leu-Leu-Arg-aldehyde) and to Cbz-Leu-Leu-Leu-aldehyde, and an example of its further optimization.

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. 

A concise alternative synthesis of the azepinones 241 has been developed based on the key ring-closing metathesis of the a-amino enones 240 (Equation 34) <2006H(67)549>. The substrate concentration was 5 x 10 3M and yields of products are given in Table 4. The azepinone 241c was then converted to a known cathepsin K inhibitor. 

---