Inhibitors cathepsin

Trifluoroethylamines can also be considered as metabolically stable amide iso-steres. A CF3 group can replace the C=0 of an amide and generates a metabolically stable, non-basic amine that maintains the excellent hydrogen bonding. This concept has been developed in the design of protease inhibitors (cathepsin K) (Fig. 18) [62]. 

An azepanone-based inhibitor, 179, of the cysteine protease inhibitor, cathepsin K, was prepared via an asymmetric synthesis from 171 and 172 (Xc = a 4(.V)-benzyloxazolidin-2-one moiety) with ring-closing metathesis of 173 then being used to complete the seven-membered ring in the intermediate 174 with a very high de (Scheme 23). Further functional group manipulations via 175-178 then resulted in 179 <2005TL2799>. 

Enzyme inhibitors (e.g. metalloproteinases, cathepsin K) Purinergic modulators... 

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... 

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]. 

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],... 

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 N-terminal sequence of one peptide from the 35 kDa zone of H-gal-GP showed some homology to cathepsin B-like cysteine proteases. Molecular cloning has also identified a thrombospondin homologue associated with the diffusely staining region between zones A and B, a galectin associated with zone D (Newlands et al., 1999) and a low molecular weight (approximately 13 kDa) cysteine protease inhibitor, cystatin. 

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>. 

Inhibitors of cysteine protease cathepsin K, for the treatment of osteoporosis, have been reported. The 1,2,4-thiadiazole derivative 131 showed nanomolar activity <2004JME5057>. 

Figure 1. 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) TIBO scaffold, E) sustiva, and F) hydroxyethylamine scaffold. The biotin derivatives," MMP inhibitors,19 TIBO analogs,21 and cathepsin D inhibitors22 derived from structures A), C), D), and F), respectively, have been published elsewhere.

NO is recognized as a mediator of bone cell metabolism, where it regulates osteoblast and osteoclast activity [141-143]. Osteoporosis, which frequently occurs in postmenopausal women, is a systemic skeletal disease associated with abnormal bone resorption. Addition of NO or NO donors to osteoclasts in vitro results in a reduction in bone resorption, whereas NO synthase inhibitors increase bone resorption, both in vitro and in vivo. Further research has shown that NO reduces bone resorption, via inhibition of the cysteine protease cathepsin K, which is believed to be a key protease in bone resorption. Most of the NO donors, i.e., nitroglycerin, 3-... 

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