Effects of ONO-5334, a novel orally-active inhibitor of cathepsin K, on bone metabolism

Ochi, Yasuo; Yamada, Hiroyuki; Mori, Hiroshi; Nakanishi, Yasutomo; Nishikawa, Satoshi; Kayasuga, Ryoji; Kawada, Naoki; Kunishige, A.; Hashimoto, Yoshiaki; Tanaka, Makoto; Sugitani, Masafumi; Kawabata, Kazuhito

doi:10.1016/j.bone.2011.09.041

Cited by 41 publications

(35 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus far, it has been shown to reduce markers of bone resorption without significant effects on bone formation or osteoclast viability and was well tolerated (Ochi et al , 2011 ;Nagase et al , 2012a,b ). The molecule contains a α -ketoamide warhead and even though it appears much less selective than odanacatib (Table 1) no off-target effects have been reported thus far.…”

Section: Targeting Of Cathepsin K For the Treatment Of Osteoporosismentioning

confidence: 95%

Cathepsin K: a unique collagenolytic cysteine peptidase

Novinec

Lenarčič²

2013

Biological Chemistry

119

View full text Add to dashboard Cite

Cathepsin K has emerged as a promising target for the treatment of osteoporosis in recent years. Initially identified as a papain-like cysteine peptidase expressed in high levels in osteoclasts, the important role of this enzyme in bone metabolism was highlighted by the finding that mutations in the CTSK gene cause the rare recessive disorder pycnodysostosis, which is characterized by severe bone anomalies. At the molecular level, the physiological role of cathepsin K is reflected by its unique cleavage pattern of type I collagen molecules, which is fundamentally different from that of other endogenous collagenases. Several cathepsin K inhibitors have been developed to reduce the excessive bone matrix degradation associated with osteoporosis, with the frontrunner odanacatib about to successfully conclude Phase 3 clinical trials. Apart from osteoclasts, cathepsin K is expressed in different cell types throughout the body and is involved in processes of adipogenesis, thyroxine liberation and peptide hormone regulation. Elevated activity of cathepsin K has been associated with arthritis, atherosclerosis, obesity, schizophrenia, and tumor metastasis. Accordingly, its activity is tightly regulated via multiple mechanisms, including competitive inhibition by endogenous macromolecular inhibitors and allosteric regulation by glycosaminoglycans. This review provides a state-of-the-art description of the activity of cathepsin K at the molecular level, its biological functions and the mechanisms involved in its regulation.

show abstract

Section: Targeting Of Cathepsin K For the Treatment Of Osteoporosismentioning

confidence: 95%

Cathepsin K: a unique collagenolytic cysteine peptidase

Novinec

Lenarčič²

2013

Biological Chemistry

119

View full text Add to dashboard Cite

show abstract

“…The compound had cathepsin K specificity, but lysosomotropic properties due to basicity may have decreased cathepsin K specificity and resulted in the safety problems [39]. Odanacatib and ONO-5334 [40,13] have subsequently been evaluated and both increase BMD without safety concerns [13,17,40,41].…”

Section: Accepted Manuscriptmentioning

confidence: 98%

“…ONO-5334 is a competitive and reversible cathepsin K inhibitor [13]. Based on cathepsin K cleavage sites on type I collagen [8,9], the number of cathepsin K cleavage sites on type I collagen that generate crosslinks NTX and CTX are the same.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

See 1 more Smart Citation

An oral cathepsin K inhibitor ONO-5334 inhibits N- terminal and C- terminal collagen crosslinks in serum and urine at similar plasma concentrations in postmenopausal women

Tanaka

Hashimoto

Hasegawa

2015

Bone

Self Cite

View full text Add to dashboard Cite

“…Three of the cathepsin K inhibitors that did not progress beyond phase I and phase II clinical trials are balicatib (AAE-581), relacatib (SB-462795), and ONO-5334 [83][84][85].…”

Section: Cathepsin K Protease Inhibitors Including Odanacatibmentioning

confidence: 99%

Pharmacological diversity among drugs that inhibit bone resorption

Russell

2015

Current Opinion in Pharmacology

View full text Add to dashboard Cite

Effects of ONO-5334, a novel orally-active inhibitor of cathepsin K, on bone metabolism

Cited by 41 publications

References 33 publications

Cathepsin K: a unique collagenolytic cysteine peptidase

Cathepsin K: a unique collagenolytic cysteine peptidase

An oral cathepsin K inhibitor ONO-5334 inhibits N- terminal and C- terminal collagen crosslinks in serum and urine at similar plasma concentrations in postmenopausal women

Pharmacological diversity among drugs that inhibit bone resorption

Contact Info

Product

Resources

About