Balicatib, a cathepsin K inhibitor, stimulates periosteal bone formation in monkeys

Jerome, Christopher P.; Missbach, Martin; Gamse, R.

doi:10.1007/s00198-011-1529-x

Cited by 59 publications

(30 citation statements)

References 28 publications

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“…Such antiresorptive compounds could in principle meet the criteria for being classified as bone anabolics, provided they increase bone formation markers (P1NP and bone-specific alkaline phosphatase), MAR, and/or BFR while reducing markers of bone resorption (C-telopeptide of type I collagen, N-telopeptide of type I collagen). Although not meeting these criteria in humans, pharmacological inhibition of cathepsin K in animals has been reported to reduce bone resorption markers to an extent comparable to oral bisphosphonates (approximately 40%) while increasing bone formation markers in rabbits and monkeys (94,95). In human clinical trials, bone formation markers returned to near baseline (96) or were unchanged (97,98).…”

Section: Can Novel Antiresorptives Reveal An "Anabolic" Component?mentioning

confidence: 92%

Update on Bone Anabolics in Osteoporosis Treatment: Rationale, Current Status, and Perspectives

Baron

Hesse

2012

The Journal of Clinical Endocrinology & Metabolism

293

266

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Osteoporosis is defined as low bone mineral density associated with skeletal fractures secondary to minimal or no trauma, most often involving the spine, the hip, and the forearm. The decrease in bone mineral density is the consequence of an unbalanced bone remodeling process, with higher bone resorption than bone formation. Osteoporosis affects predominantly postmenopausal women, but also older men. This chronic disease represents a considerable medical and socioeconomic burden for modern societies. The therapeutic options for the treatment of osteoporosis have so far comprised mostly antiresorptive drugs, in particular bisphosphonates and more recently denosumab, but also calcitonin and, for women, estrogens or selective estrogen receptor modulators. These drugs have limitations, however, in particular the fact that they lead to a low turnover state where bone formation decreases with the decrease in bone-remodeling activity. In this review, we discuss the alternative class of osteoporosis drugs, i.e. bone anabolics, their biology, and the perspectives they offer for our therapeutic armamentarium. We focus on the two main osteoanabolic pathways identified as of today: PTH, the only anabolic drug currently on the market; and activation of canonical Wnt signaling through inhibition of the endogenous inhibitors sclerostin and dickkopf1. Each approach is based on a different molecular mechanism, but most recent evidence suggests that these two pathways may actually converge, at least in part. Whereas recombinant human PTH treatment is being revisited with different formulations and attempts to regulate endogenous PTH secretion via the calcium-sensing receptor, antibodies to sclerostin and dickkopf1 are currently in clinical trials and may prove to be even more efficient at increasing bone mass, possibly independent of bone turnover. Each of these anabolic approaches has its own limitations and safety issues, but the prospects of effective anabolic therapy for osteoporosis are indeed bright.

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Section: Can Novel Antiresorptives Reveal An "Anabolic" Component?mentioning

confidence: 92%

Update on Bone Anabolics in Osteoporosis Treatment: Rationale, Current Status, and Perspectives

Baron

Hesse

2012

The Journal of Clinical Endocrinology & Metabolism

293

266

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“…These data indicate that ODN treatment may preserve bone formation while effectively inhibiting bone resorption, in contrast to what is observed with bisphosphonate treatment. An increase in periosteal bone formation in monkeys was recently shown by Cat K inhibitor balicatib (3), previously developed by Novartis [15]. Hence, these findings suggest that inhibition of Cat K may have anabolic properties in addition to inhibition of bone resorption.…”

Section: Introductionmentioning

confidence: 81%

“…A co-crystal structure of 14 with cathepsin K nicely showed that the cyclohexyl moiety occupied the S2 pocket while the preferred cyclic amine group pointed to the S1¢ pocket. In subsequent patents, analogous pyrimidine derivatives were claimed in which the cyclohexyl amine group has been replaced with either a phenyl, preferably substituted at the 3-position (e.g., 15) [66], or a cycloheptyl moiety (16) [67]. Both compounds were reported to have IC 50 < 10 nM.…”

Section: Wijkmans and Gossenmentioning

confidence: 99%

Inhibitors of cathepsin K: a patent review (2004 – 2010)

Wijkmans

Gossen

2011

Expert Opinion on Therapeutic Patents

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Between 2004 and 2010, more than 50 patent applications have appeared, underlining the continued interest in small molecule cathepsin K inhibition for therapeutic intervention. Most compounds claimed are peptide-derived inhibitors displaying a reversible binding nitrile or ketone warhead. The success of these compounds in the clinic will be determined by the selectivity that can be achieved against other off-target cathepsin. In this respect, eliminating lysosomotropic characteristics may prove to be crucial in the design of selective cathepsin K inhibitors. During the review period, ONO-5334 and odanacatib have progressed to Phase II and Phase III clinical trials, respectively. The results of these studies are eagerly awaited and may determine the future of these agents as disease-modifying therapeutics.

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“…Inhibition of Ctsk could reduce bone resorption or even increase bone formation by osteoclast-derived factors or matrix-derived growth factors [31]. Several Ctsk inhibitors including Odanacatib [32], ONO5334 [33], balicatib [34], and relacatib [35], have been selected to enter clinical development. However, ONO5334, balicatib, and relacatib unfortunately failed in phase I or II of trials due to their side effects and other commercial reasons [36].…”

Section: Discussionmentioning

confidence: 99%

Discovery of a New Class of Cathepsin K Inhibitors in Rhizoma Drynariae as Potential Candidates for the Treatment of Osteoporosis

Qiu

Dong

Dai

et al. 2016

IJMS

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Rhizoma Drynariae (RD), as one of the most common clinically used folk medicines, has been reported to exert potent anti-osteoporotic activity. The bioactive ingredients and mechanisms that account for its bone protective effects are under active investigation. Here we adopt a novel in silico target fishing method to reveal the target profile of RD. Cathepsin K (Ctsk) is one of the cysteine proteases that is over-expressed in osteoclasts and accounts for the increase in bone resorption in metabolic bone disorders such as postmenopausal osteoporosis. It has been the focus of target based drug discovery in recent years. We have identified two components in RD, Kushennol F and Sophoraflavanone G, that can potentially interact with Ctsk. Biological studies were performed to verify the effects of these compounds on Ctsk and its related bone resorption process, which include the use of in vitro fluorescence-based Ctsk enzyme assay, bone resorption pit formation assay, as well as Receptor Activator of Nuclear factor κB (NF-κB) ligand (RANKL)-induced osteoclastogenesis using murine RAW264.7 cells. Finally, the binding mode and stability of these two compounds that interact with Ctsk were determined by molecular docking and dynamics methods. The results showed that the in silico target fishing method could successfully identify two components from RD that show inhibitory effects on the bone resorption process related to protease Ctsk.

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Balicatib, a cathepsin K inhibitor, stimulates periosteal bone formation in monkeys

Abstract: Balicatib partially prevented ovariectomy-induced changes in bone mass, inhibited bone turnover at most sites, and had an unexpected stimulatory effect on periosteal bone formation.

Cited by 59 publications

References 28 publications

Update on Bone Anabolics in Osteoporosis Treatment: Rationale, Current Status, and Perspectives

Update on Bone Anabolics in Osteoporosis Treatment: Rationale, Current Status, and Perspectives

Inhibitors of cathepsin K: a patent review (2004 – 2010)

Discovery of a New Class of Cathepsin K Inhibitors in Rhizoma Drynariae as Potential Candidates for the Treatment of Osteoporosis

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