The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K

Gauthier, Jacques Yves; Chauret, Nathalie; Cromlish, Wanda; Desmarais, Sylvie; Duong, Le T.; Falgueyret, Jean‐Pierre; Kimmel, Donald B.; Lamontagne, Sonia; Léger, Serge; LeRiche, Tammy; Li, Chun Sing; Massé, Frédéric; McKay, Daniel J.; Nicoll‐Griffith, Deborah A.; Oballa, Renata M.; Palmer, James T.; Percival, M. David; Riendeau, Denis; Robichaud, Jacques; Rodan, Gideon A.; Rodan, Sevgi B.; Seto, Carmai; Thérien, Michel; Truong, Vouy-Linh; Venuti, Michael C.; Wesolowski, Gregg; Young, Robert N.; Zamboni, Robert; Black, W. Cameron

doi:10.1016/j.bmcl.2007.12.047

Cited by 423 publications

(291 citation statements)

References 21 publications

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“…Despite the above drawback of L-235, this inhibitor showed potency equivalent to our clinical candidate ODN against the human CatK (IC 50 of $0.2 nmol/L; ref. 18), but has an approximately 50-fold shift in potency against the rat enzyme while ODN is not active in rodent. Because the effective dose of ODN at 5 mg p.o., daily provided mean plasma concentration of 512 AE 203 nmol/L in patients with breast cancer (16) and due to the relatively short half-life of L-235 in rodent, we thus selected L-235 at 10, 30, and 100 mg/ kg twice-daily, which provided the mean plasma concentrations of 10.4, 35.6, and 166.2 (mmol/L)Áh, respectively, in the rats.…”

Section: Discussionmentioning

confidence: 99%

“…To further our understanding on the potential benefits and mechanisms of the CatK inhibitors compared with the bisphosphonates for the treatment of MBD, we selected L-006235 (L-235) as a proof-of-concept CatKi for evaluation in various rodent models of metastatic disease. The reversible CatKi, L-235, is structurally related to ODN (17,18). This compound inhibits human CatK with a Ki of 0.25 nmol/L, and is >4,000-fold selective against other human cathepsins L, B, and S (17).…”

Section: Introductionmentioning

confidence: 99%

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Efficacy of a Cathepsin K Inhibitor in a Preclinical Model for Prevention and Treatment of Breast Cancer Bone Metastasis

Duong

Wesolowski

Leung

et al. 2014

Molecular Cancer Therapeutics

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Cathepsin K (CatK) is essential for osteoclast-mediated bone resorption. CatK expression is also detected in breast cancer cells that metastasize to bone. Here, the CatK inhibitor L-235 dosed in prevention (10, 30, and 100 mg/kg, p.o., b.i.d.) or treatment regimen (30 mg/kg) was compared with the bisphosphonate zoledronic acid (ZOL, 7.5 mg/kg/wk, s.c.) in the intratibial injection model of MDA-MB-231 breast carcinoma in nude rats. Progression of osteolysis, skeletal tumor burden, and local metastasis was evaluated by radiography through 42 days and ex vivo mCT and histology. IHC and RT-PCR confirmed the increases in CatK protein and mRNA levels in human breast cancer primary and metastatic tumors. In the experimental model of breast cancer bone metastasis, L-235 dosed in preventive mode resulted in a dose-related reduction of osteolysis of 72%, 75%, and 87% respectively, compared with ZOL by 86% versus intact. Similarly, L-235 significantly reduced intratibial tumor volume by 29%, 40%, and 63%, respectively, compared with 56% by ZOL versus vehicle. Efficacy of L-235 and ZOL on reduction of osteolytic lesions and tumor burden was comparable in treatment versus preventive regimens. All L-235 doses inhibited cortical disruption and extraskeletal tumor growth to a level comparable with ZOL. Assessment of local metastasis demonstrated that treatment with the CatK inhibitor was more effective than ZOL in reducing breast cancer invasion. These data support the role of CatK in breast cancer skeletal growth and metastasis and CatK inhibitors may represent a novel oral therapy for treatment of metastatic breast cancer. Mol Cancer Ther; 13(12); 2898-909. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Efficacy of a Cathepsin K Inhibitor in a Preclinical Model for Prevention and Treatment of Breast Cancer Bone Metastasis

Duong

Wesolowski

Leung

et al. 2014

Molecular Cancer Therapeutics

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“…Inhibition of catK activity would be expected to inhibit this matrix degradation and interfere with bone resorption, and catK inhibitors have been developed and tested as potential therapies to treat osteoporosis. (2)(3)(4)(5)(6)(7) ODN is a selective inhibitor of catK that is effective when administered orally with weekly dosing without regard to food intake. Inhibition of catK enzyme activity by ODN is a reversible process, and other osteoclast activities do not appear to be greatly affected.…”

Section: Discussionmentioning

confidence: 99%

“…Since catK is expressed primarily in osteoclasts, inhibition of this enzyme to reduce bone resorption is being explored as a pharmacologic treatment for osteoporosis. (2)(3)(4)(5)(6)(7) Recent advances have led to the discovery of drugs that selectively inhibit either acid secretion (8)(9)(10) or catK activity. (2)(3)(4)(5)11,12) Some early catK inhibitors proved to have crossreactivity with other cathepsins, (5,13,14) and cutaneous adverse events were reported for one.…”

Section: Introductionmentioning

confidence: 99%

“…Treatment with ODN decreases bone resorption by selectively inhibiting proteolysis of matrix protein by catK without affecting other osteoclast activities or osteoclast viability. (6,7) A dose-ranging study in postmenopausal women with low BMD showed that ODN treatment progressively increased BMD, decreased bone-resorption biomarkers (with lesser effect on bone-formation biomarkers), did not suppress TRACP 5b, and was generally well tolerated over 2 years. (16) This study is a 1-year extension of that dose-ranging study.…”

Section: Introductionmentioning

confidence: 99%

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Odanacatib in the treatment of postmenopausal women with low bone mineral density: Three-year continued therapy and resolution of effect

Eisman

Bone²,

Hosking

et al. 2010

Journal of Bone and Mineral Research

229

147

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The selective cathepsin K inhibitor odanacatib (ODN) progressively increased bone mineral density (BMD) and decreased boneresorption markers during 2 years of treatment in postmenopausal women with low BMD. A 1-year extension study further assessed ODN efficacy and safety and the effects of discontinuing therapy. In the base study, postmenopausal women with BMD T-scores between À2.0 and À3.5 at the lumbar spine or femur received placebo or ODN 3, 10, 25, or 50 mg weekly. After 2 years, patients (n ¼ 189) were rerandomized to ODN 50 mg weekly or placebo for an additional year. Endpoints included BMD at the lumbar spine (primary), total hip, and hip subregions; levels of bone turnover markers; and safety assessments. Continued treatment with 50 mg of ODN for 3 years produced significant increases from baseline and from year 2 in BMD at the spine (7.9% and 2.3%) and total hip (5.8% and 2.4%). Urine cross-linked N-telopeptide of type I collagen (NTx) remained suppressed at year 3 (À50.5%), but bone-specific alkaline phosphatase (BSAP) was relatively unchanged from baseline. Treatment discontinuation resulted in bone loss at all sites, but BMD remained at or above baseline. After ODN discontinuation at month 24, bone turnover markers increased transiently above baseline, but this increase largely resolved by month 36. There were similar overall adverse-event rates in both treatment groups. It is concluded that 3 years of ODN treatment resulted in progressive increases in BMD and was generally well tolerated. Bone-resorption markers remained suppressed, whereas bone-formation markers returned to near baseline. ODN effects were reversible: bone resorption increased transiently and BMD decreased following treatment discontinuation. ß

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The Design and Application of Bioisosteres in Drug Design

Meanwell

2021

Burger's Medicinal Chemistry and Drug Discovery

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Bioisosterism, the design of structural motifs that emulate established functionality to effect a biological response, has evolved into a powerful design principle in medicinal chemistry and drug discovery that can be implemented to address issues associated with intrinsic potency and/or a range of developability challenges. While bioisosterism has its origins in the concept of isosterism, which was invoked to explain the similarity of physicochemical properties between molecules with analogous size and shape, the contemporary interpretation of bioisosterism extends well beyond this simple definition to encompass relationships that reflect a recapitulation of biological properties by molecules that can be structurally quite disparate. This article provides a synopsis of established and emerging bioisosteric relationships that are discussed in the context of applications to solving problems in drug discovery and development. Bioisosteres that are described range from the replacement of hydrogen atoms by deuterium or fluorine to more esoteric higher order bioisosteres that convene intricate arrays of functionality. These are considered nonclassical in nature and offer functional mimesis of a range of simple and complex functionalities encompassing exchangeable groups, cyclic/noncyclic substructures capable of mimicking rings, and extends to include drug–water and drug–metal complexes.

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The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K

Cited by 423 publications

References 21 publications

Efficacy of a Cathepsin K Inhibitor in a Preclinical Model for Prevention and Treatment of Breast Cancer Bone Metastasis

Efficacy of a Cathepsin K Inhibitor in a Preclinical Model for Prevention and Treatment of Breast Cancer Bone Metastasis

Odanacatib in the treatment of postmenopausal women with low bone mineral density: Three-year continued therapy and resolution of effect

The Design and Application of Bioisosteres in Drug Design

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