P2–P3 conformationally constrained ketoamide-based inhibitors of cathepsin K

Barrett, David; Boncek, Virginia; Catalano, John G.; Deaton, David N.; Hassell, Anne M.; Jurgensen, Cynthia H.; Long, Stacey T.; McFadyen, Robert B.; Miller, A. Whitman; Miller, Larry R.; Payne, J. Alan; Ray, John A.; Sámano, Vicente; Shewchuk, Lisa M.; Tavares, Francis X.; Wells‐Knecht, Kevin J.; Willard, Derril H.; Wright, Laura; Zhou, Hongmin

doi:10.1016/j.bmcl.2005.05.062

Cited by 32 publications

(20 citation statements)

References 17 publications

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“…Pycnodysostosis, which is due to inactivating mutations of CatK in humans, leads to an increase in bone mass [Chavassieux et al 2008], but is also associated with an increased risk of fragility fracture, in particular atypical subtrochanteric fracture of the femur, suggesting that the bone quality is impaired. Reductions in biochemical markers of bone resorption and increased bone mineral density (BMD) have been shown by pharmacological inhibition of CatK in rats and monkeys [Barrett et al 2005;Kumar et al 2007]. Non lysosomotropic inhibitors may be better than lysosomotropic inhibitors because they do not accumulate in the lysosomes of all cells.…”

Section: What Is a Cathepsin K Inhibitor?mentioning

confidence: 99%

Odanacatib: a review of its potential in the management of osteoporosis in postmenopausal women

Chapurlat

2015

Therapeutic Advances in Musculoskeletal

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Odanacatib is a cathepsin K inhibitor developed for the treatment of postmenopausal osteoporosis. It is a bone resorption inhibitor, but which preserves bone formation to some extent. It can be administered once a week, in tablets also containing vitamin D. In a large clinical development program, it has been shown that odanacatib reduces bone resorption, with a reduction of about 60-70% in biochemical markers of resorption, while bone formation decreases to a lesser magnitude. Odanacatib continuously increases bone mineral density (BMD) at the hip and lumbar spine over 5 years. Once it is stopped, a complete resolution of effect is observed, with declining BMD and increased bone turnover. Bone microarchitecture and bone strength have also been improved in clinical trials using quantitative computed tomography (QCT) at the lumbar spine and hip, and high resolution peripheral QCT at the distal radius and tibia. In a phase III trial involving 16,713 postmenopausal women ⩾65 years of age with low BMD, the risk of fragility fracture was significantly reduced at the spine, hip and other nonvertebral sites compared with the placebo group. Odanacatib has been generally well tolerated, with no observation of osteonecrosis of the jaw so far, but with exceptional observations of subtrochanteric atypical fracture and morphea-like lesions. Odanacatib appears a useful new option in the treatment of postmenopausal osteoporosis.

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Section: What Is a Cathepsin K Inhibitor?mentioning

confidence: 99%

Odanacatib: a review of its potential in the management of osteoporosis in postmenopausal women

Chapurlat

2015

Therapeutic Advances in Musculoskeletal

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“…the larger S 2 pockets for cathepsins S and L versus the shallower S 2 pocket of cathepsin K, in combination with differences in S 3 subsites can afford selective cathepsin K inhibitors [129,165,150]. Selectivity gains using the S 1 prime subsite have also been reported for the ketoamide class of inhibitors [152,153]. Finally, in the design of cathepsin K inhibitors, sequence identity/homology among species needs to be considered so that a suitable pharmacodynamic model can be utilized to assist translation to the clinic.…”

Section: Introductionmentioning

confidence: 93%

“…The irreversible nonselective cysteine protease inhibitor E-64 attenuates osteoclastic bone resorption [148,149]. Furthermore, cathepsin K specific inhibitors, such as cyclic ketones [150,151], ketoamides [152,153], and dipeptidyl nitriles [154], exhibit in vivo activity when administered orally to either rodents or primates. Finally, several pharmaceutical companies are currently performing clinical trials, with Novartis having reported reductions in bone resorption markers in humans with one selective cathepsin K inhibitor [155,156].…”

Section: Introductionmentioning

confidence: 99%

“…At the same time as the structural screening and synthetic complexity reduction efforts were being investigated, the effect of conformational constraint of the P 2 /P 3 linker of analog 143 was also explored [153]. As shown in Table 32, initial inhibitor design involved replacement of the flexible P 2 -P 3 tether with various heterocyclic ring systems in the hope of improving potency, selectivity, and/or pharmacokinetic properties.…”

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confidence: 99%

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Design of Cathepsin K Inhibitors for Osteoporosis

Deaton

Tavares²

2005

CTMC

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Osteoporosis is a progressive, debilitating bone disease resulting in increased cost and morbidity to the elderly. This review summarizes the therapeutic approaches taken in the treatment of osteoporosis with particular emphasis on cathepsin K inhibitors. Cathepsin K, a cysteine protease predominantly expressed in osteoclasts, is a key player involved in bone matrix degradation. Both genetic ablation and small molecule inhibitor strategies versus cathepsin K have validated the importance of this enzyme in bone resorption. Starting from aldehyde-based leads, this review synopsizes the design of improved small molecule inhibitors by GlaxoWellcome researchers. These efforts involved the evaluation of various warheads, including cyanamides, ketoheterocycles, and ketoamides. Initial structure/activity relationships of aldehyde-based inhibitors proved useful in the design of ketoamide-based cathepsin K inhibitors. Further exploration of S(3), S(2), S(1), and S(1') subsites with P(3), P(2), P(1), and P(1') probes have resulted in the identification of potent, selective, orally bioavailable ketoamide-based inhibitors of cathepsin K with demonstrated in vivo efficacy.

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“…In this application, the synthesis of a large number of diketohydrazines was exemplified, however, only biological data were provided for analog 37 (IC 50 : Cat K 4.9 nM, Cat B 60 nM, Cat S 30 nM, Cat L 79 nM). Although ONO-5334 has been claimed to show potent and selective inhibition of Cat K, the results of 37 suggests that the selectivity profile of this class of compounds may be rather limited, a liability that was also featured by other optimized a-ketoamides [103]. In two additional Ono patents further analogs of ONO-5334 have been claimed [104,105].…”

Section: Ketone-based Inhibitorsmentioning

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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P2–P3 conformationally constrained ketoamide-based inhibitors of cathepsin K

Cited by 32 publications

References 17 publications

Odanacatib: a review of its potential in the management of osteoporosis in postmenopausal women

Odanacatib: a review of its potential in the management of osteoporosis in postmenopausal women

Design of Cathepsin K Inhibitors for Osteoporosis

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

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