Discovery and parallel synthesis of a new class of cathepsin k inhibitors

Smith, Roger A.; Bhargava, Ajay; Browe, Christopher; Chen, Jinshan; Dumas, Jacques; Hatoum‐Mokdad, Holia; Romero, Romulo H.

doi:10.1016/s0960-894x(01)00600-x

Cited by 16 publications

(17 citation statements)

References 18 publications

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“…(14); the -alkoxyketone derivatives 42 (K i = 11 nM) and 43 (K i = 8 nM) [198,199], the peptidomimetic aminomethyl ketone 44 (IC 50 = 230 nM) [200], and the pyridoxal propionate derivatives Clik-164 (low μM range) [59].…”

Section: Cathepsin K Inhibitorsmentioning

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: Cathepsin K Inhibitorsmentioning

confidence: 99%

Thiol Proteases: Inhibitors and Potential Therapeutic Targets

Leung-Toung

Zhao²,

Li³

et al. 2006

CMC

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“…Addition of Clik-164 (53) dramatically suppressed pit formation by rat osteoclasts in vivo. Interestingly, in the A new class of cathepsin K inhibitors, namely peptidomimetic aminomethyl ketones, was discovered through a high-throughput screening of an in-house compound collection [139]. Thus, the aminomethyl ketone moiety acts as the electrophilic isostere as exemplified by compound 56 shown Fig.…”

Section: Cathepsin K Inhibitorsmentioning

confidence: 99%

Thiol-Dependent Enzymes and Their Inhibitors: A Review

Leung-Toung

Li²,

Tam³

et al. 2002

CMC

129

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Biological thiol-dependent enzymes have recently received extensive attention in the literature because of their involvement in a variety of physiopathological conditions. The active thiol groups of these enzymes are derived from the cysteine residues present. Hence, in a biological system, the selective reversible or irreversible inhibition of the activity of these enzymes by modification of the thiol moiety may potentially lead to the development of a chemotherapeutic treatment. Despite all the research efforts involved in the attempt to develop potential chemotherapeutic treatments for the major diseases involving cysteine proteases, there are in fact no such treatments available yet. However, AG7088 (1) an inhibitor of rhinovirus-3C is in phase II/III clinical trial for the treatment of common cold and VX-740 (2, pralnacasan) an inhibitor of caspase-1 is in phase II clinical trial as an anti-inflammatory agent for rheumatoid arthritis. Several other cysteine protease inhibitors (i.e., cathepsin K, and S) are in pre-clinical evaluation or pre-clinical development. Structure-based drug design approaches have been instrumental in the development of these inhibitors. Intensive biochemical studies on the cysteine proteases have shed some light on some potential targets for therapeutic development. In addition, new techniques and new ideas are constantly emerging. As such, an up-to-date review of the literature on thiol-dependent enzymes as potential targets and their inhibitors designed from peptidic, modified peptidomimetic scaffolds and from small heterocyclic molecules is presented.

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“…Note that the distri-bution of STR1236 (Fig. 2B) is clearly bimodal, with major alleles at 10 RUs (62% frequency) and 19 RUs (25% frequency), but with alleles rarely observed at intervening sizes of [12][13][14][15][16] RUs. This suggests that the two STR1236 modes have distinct population histories, a hypothesis that seems to be supported by the observation that alleles of the two modes are usually carried on different haplotypic backgrounds (Table 3; Fig.…”

Section: Allele and Genotype Frequencies For Ctsk Polymorphismsmentioning

confidence: 95%

“…(8) Given the increasing body of evidence linking CTSK with the regulation of bone density, CTSK is an attractive drug target for the treatment of osteoporosis, and several cathepsin K inhibitors have been identified, including peptide-based ␣,␣Ј-diacylamino ketones, (9) pyridoxal propionate derivatives, (10) cyanamides, (11) alkoxymethyl ketones, (12) and peptidomimetic aminomethyl ketones. (13) Promisingly, CTSK inhibitor SB-357114 has recently been shown to inhibit bone resorption in estrogen-deficient cynomolgus monkeys. (14) Although CTSK deficiency has been shown to be responsible for the severe monogenic bone disorder pychodysostosis, no studies of common genetic variation in the CTSK gene and the impact of such variation on bone density in the general population have been reported.…”

Section: Introductionmentioning

confidence: 99%

Characterization of Common Genetic Variants in Cathepsin K and Testing for Association With Bone Mineral Density in a Large Cohort of Perimenopausal Women From Scotland

Giraudeau

McGinnis

Gray

et al. 2004

Journal of Bone and Mineral Research

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BMD values in ϳ3000 perimenopausal Scottish women were adjusted by regression to identify and account for nongenetic factors. Adjusted BMD values were not associated with simple tandem repeat (STR) markers or single nucleotide polymorphisms (SNPs) at the Cathepsin K (CTSK) locus. We present a thorough analysis of common CTSK polymorphisms and genetic relatedness among CTSK haplotypes.Introduction: CTSK is a cysteine protease of the papain family and is thought to play a critical role in osteoclastmediated bone degradation. Rare, inactivating mutations in CTSK cause pychodysostosis, an autosomal recessive osteochondrodysplasia characterized by osteosclerosis and short stature. However, there have been no studies of common genetic variants in CTSK and their possible association with bone density in the general population. Materials and Methods: To identify common single nucleotide polymorphisms (SNPs) and simple tandem repeat (STR) polymorphisms in and around CTSK, we screened all CTSK exons, intron A, all intron-exon boundaries, and the putative CTSK promoter region in 130 random whites using both high-performance liquid chromatography (HPLC) and DNA sequencing. CTSK markers were genotyped in ϳ3000 perimenopausal Scottish women whose hip and spine bone mineral density (BMD) had been measured by DXA. We performed linear regression analysis to identify and adjust for nongenetic predictors of BMD, and adjusted BMD values (regression residuals) were tested for association with individual CTSK markers and haplotypes by ANOVA and the composite haplotype method of Zaykin et al. Results and Conclusions:We discovered two intronic SNPs (8% and 9% frequency), but no common exonic SNPs (Ͼ1% frequency), and found that three STRs at the immediate 5Ј end of the CTSK locus are highly polymorphic. The population frequencies of haplotypes defined by these five polymorphisms were estimated, and a cladogram was derived showing proximity of relationship and likely descent of the 30 most common CTSK haplotypes. Regression analyses revealed that approximately 39% of spine and 19% of hip rate of change in BMD was accounted for by nongenetic factors. For baseline BMD values in premenopausal women, nongenetic predictors explained 11% of the variance at the spine and 13% at the hip. Adjusted BMD values showed no statistically significant association with any of the individual CTSK polymorphisms or CTSK haplotypes.

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Discovery and parallel synthesis of a new class of cathepsin k inhibitors

Cited by 16 publications

References 18 publications

Thiol Proteases: Inhibitors and Potential Therapeutic Targets

Thiol Proteases: Inhibitors and Potential Therapeutic Targets

Thiol-Dependent Enzymes and Their Inhibitors: A Review

Characterization of Common Genetic Variants in Cathepsin K and Testing for Association With Bone Mineral Density in a Large Cohort of Perimenopausal Women From Scotland

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