1,2,4-Thiadiazole: A novel Cathepsin B inhibitor

Leung-Toung, Régis; Wodzinska, Jolanta; Li, Wanren; Lowrie, Jayme; Kukreja, Rahul; Désilets, Denis; Karimian, Khashayar; Tam, Tim F.

doi:10.1016/j.bmc.2003.09.040

Cited by 73 publications

(41 citation statements)

References 48 publications

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“…(3) illustrates the structure of heterocyclic [1,2,4]-thiadiazole, a new electrophilic warhead, for the irreversible inactivation of cathepsin B. The enzyme cysteine thiol attacked the sulphur atom in the heterocyclic ring to form a disulphide bond with concomitant ring opening [30,166]. Substituents at the X position strongly influenced the enzyme binding affinity (K i : OMe>Ph>COOH), while the substituents at the Y position acted as the recognition arm for enzyme selectivity.…”

Section: Physiological Role and Potential Therapeutic Targetsmentioning

confidence: 99%

Thiol Proteases: Inhibitors and Potential Therapeutic Targets

Leung-Toung

Zhao²,

Li³

et al. 2006

CMC

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A better understanding of the biological roles and the pathological consequences of thiol-dependent enzymes has emerged in recent years, and hence considerable progress has been made in identifying and delineating cysteine proteases that can be considered promising drug targets from those involved in housekeeping functions. Cysteine proteases have been implicated in a wide variety of disease processes ranging from cardiovascular, inflammatory, viral and immunological disorders to cancer. The first milestone in drug development of cysteine protease inhibitors has probably been reached, as IDN-6556 (a broad spectrum caspase inhibitor) has recently received Orphan Drug label by the U.S. Food and Drug Administration for use in the treatment of the patients undergoing liver transplantation and other solid organ transplantation. IDN-6556, which blocks apoptosis, is in Phase II human clinical trial in patients undergoing liver transplantation. In addition, more than ten cysteine protease inhibitors are presently at various phases of clinical development/trials for diverse diseases. This review emphasises on the new development from the literature reports since the year 2000 in the exploration of potential cysteine proteases as prospective drug targets, and the investigation of promising inhibitors that can potentially be developed for the treatment of human diseases. Transglutaminases, another class of thiol-dependent enzymes, are not discussed here.

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Section: Physiological Role and Potential Therapeutic Targetsmentioning

confidence: 99%

Thiol Proteases: Inhibitors and Potential Therapeutic Targets

Leung-Toung

Zhao²,

Li³

et al. 2006

CMC

Self Cite

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“…(9)). This feature offers several advantages for these 1,2,4-thiadiazoles over other classes of catB inhibitors because the housekeeping function of intracellular catB is again left intact, with only extracellular catB being inhibited [132]. The opposite is true for electron donating substituents [91,131].…”

Section: The 124-thiadiazole Cathepsin B Inhibitorsmentioning

confidence: 99%

Inhibitors of Cathepsin B

Frlan

Gobec²

2006

CMC

104

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Cathepsin B is an abundant and ubiquitously expressed cysteine peptidase of the papain family. It is involved in many physiological processes, such as remodeling of the extracellular matrix (wound healing), apoptosis, and activation of thyroxine and renin. In addition to its physiological roles, cathepsin B is important in many pathological processes, such as inflammation, parasite infection and cancer, where it is highly up-regulated. In cancer patients, elevated cathepsin B activity correlates to poor therapy outcome. Therefore, it is not surprising that the use of cathepsin B inhibitors reduces both tumor cell motility and invasiveness in vitro. This review summarizes recent developments in cathepsin B inhibition. To date, numerous protein inhibitors of cathepsin B have been described, some of which are of endogenous origin and function as regulators of cathepsin B activity in the cell, such as the cystatins. In addition, some exogenous protein inhibitors of cathepsin B have been isolated from various natural sources, and the use of X-ray crystal structures of cathepsin B complexed with such protein inhibitors has resulted in the design and synthesis of many new small-molecular-weight compounds as inhibitors of cathepsin B. These synthetic compounds generally contain an electrophilic functionality that reacts with cathepsin B. In the present review, these inhibitors are divided according to their mechanisms of action, as reversible and irreversible, and then further subdivided into groups for their full descriptions.

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“…Thiadiazoles and their derivatives have applications in medicinal chemistry as pharmacophores. Some examples are the use of 1,2,4-thiadiazole derivatives as novel cathepsin inhibitors [13] and in the design of inhibitors targeting the cysteine residues of proteins [14]. A recent review has been published on therapeutic applications of 1,2,4-thiadiazole heterocycles [15].…”

Section: Introductionmentioning

confidence: 99%

CBS-QB3 calculation of quantum chemical molecular descriptors of isomeric thiadiazoles

Glossman‐Mitnik

2006

Journal of Molecular Graphics and Modelling

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1,2,4-Thiadiazole: A novel Cathepsin B inhibitor

Cited by 73 publications

References 48 publications

Thiol Proteases: Inhibitors and Potential Therapeutic Targets

Thiol Proteases: Inhibitors and Potential Therapeutic Targets

Inhibitors of Cathepsin B

CBS-QB3 calculation of quantum chemical molecular descriptors of isomeric thiadiazoles

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