Cysteine proteases cathepsin

More recently, miraziridine A (113) was isolated from a marine sponge related to Theonella mirabilis and shown to inhibit the cysteine protease cathepsin B. It has been shown that the aziridine ring plays a key role in this biological activity and gives rise to irreversible inhibition of cathepsins B and L, presumably through... 

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>. 

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-... 

Figure 7. Two examples of irreversible inactivators that are not suicide substrates a) TPCK, a classic" affinity label of the serine protease chymotrypsin, b) ZFK-CH2-mesitoate, a quiescent" affinity label of the cysteine protease cathepsin B, and c) the kinetic scheme for both forms of affinity label-inactivation.

T. A., Levy, M. A. and Veber, D.F. (1998). Conformation-ally constrained 1,3-diamino ketones a series of potent inhibitors of the cysteine protease cathepsin K. /. Med. Chem. 41, 3563-3567. 

One of the goals of synthetic medicinal chemistry is to design potent inilibitors of clinically important proteases. Elastase inhibitors may be useful for treatment of emphysema, pancreatitis, and arthritis,a/b while inhibitors of the angiotensinogen-converting enzyme or of renin (Box 22-D) can help control blood pressure. Inhibition of thrombin, factor Xa, or other blood clotting factors (Fig. 12-17) may prevent blood clots and inhibition of the cytosolic tryptase may provide a new treatment for asthma. Inhibition of the cysteine protease cathepsin K may help combat osteoporosis and inhibition of cysteine proteases of corona viruses may fight the common cold. Cysteine proteases of schistosomes are also targets for protease inhibitors.c... 

The cysteine proteases cathepsin B, L, K, and S are involved in diseases such as osteoporosis, cancer metastasis, rheumatoid arthritis, and infectious diseases [352-357]. Thus, the proteases became an important target for developing inhibitors as therapeutic agents [358-363]. 

Cysteine proteases, cathepsin B, L, K, and S, may be involved in a variety of pathogenic conditions including rheumatoid arthritis, osteoporosis, and cancer metastasis, and are important targets for the development of inhibitors. The 4-oxa-l-azabicyclo[3.2.0]heptan-7-one 518 is an excellent inhibitor of cathepsin L and K in vitro <2002BML3413>. 

Proteases are essential for the conversion of inactive proprotein precursors into the active neuropeptides. Two main protease pathways have been elucidated for processing proneuropeptides and hormones the recently discovered cysteine protease cathepsin L with aminopeptidase B and the well-established subtilisin-like serine proteases that consist of prohormone con-vertases 1 and 2 followed by carboxypeptidase E/H. Endogenous regulators modulate these two protease pathways as endogenous peptide inhibitors, activators, and in vivo secretory vesicle proteins. Neuropeptides in CSE (cerebrospinal fluid) in neurological diseases can monitor brain nervous activity because neuropeptides represent active neurotransmission (93, 94). 

First, cocktails of pure, high-quality compounds will reduce the number of screening points and will, therefore, reduce cost and increase speed. A full HTS of 64 000 compounds toward human cysteine protease cathepsin B has been compared with a screen with 10 compounds per well, which had been orthogonally selected [175]. The results of both strategies were comparable. 

Unlike the well-described cysteine proteases cathepsin S (CatS) and cathepsin L (CatL), the serine protease cathepsin A (CatA) is less well known in the scientific community as a potential drug target. We became aware of pharmacological studies conducted during the 1990s with the natural product ebelactone B [1]. These studies postulated therapeutic benefits in cardiovascular diseases after CatA inhibition. Based on these reports, we started our own research program for small-molecule inhibitors of CatA and we published some of oiu" results in two research articles [2,3]. In this chapter, we will provide the reader with an in-depth discussion of our lead discovery strategy and include a siunmary of our results. 

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