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Purity: ≥98%
Odanacatib (also known as MK-0822) is a potent, neutral, and selective inhibitor of human/rabbit cathepsin K that may be applied to the management of bone metastases and osteoporosis. With IC50s of 0.2 nM/1 nM, it inhibits cathepsin K (human/rabbit) and shows good selectivity against off-target cathepsins B, L, and S. Odanacatib binds to cathepsin K specifically and inhibits its activity. This may reduce bone resorption, improve bone mineral density, and reverse osteoporotic changes. Approximately 16,000 postmenopausal osteoporosis patients are participating in a phase III trial to assess the potential of odanacatib to reduce fracture risk.
| Targets |
Cathepsin K(human) (IC50 = 0.2 nM); Cathepsin K(human) (IC50 = 1 nM)
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| ln Vitro |
Odanacatib exhibits strong cathepsin K inhibitory activity and selectivity in vitro, with IC50 values for human and rabbit cathepsin K of 0.2 nM and 1 nM, respectively. Additionally, with a corrected IC50 of 5 nM, odanacatib demonstrates comparable potencies in whole human cell enzyme occupancy assays.[1] Odanacatib reduces osteoclast (OC) resorption activity by blocking intracellular vesicular trafficking, according to a recent study.[2]
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| ln Vivo |
Odanacatib (10 mg/kg) in preclinical rats shows good pharmacokinetics with low volume of distribution (Vdss: 1.1 L kg-1), half-life (T1/2: 6 hours), oral bioavailability (F: 8%), and clearance (Cl: 2 mL kg-1 min-1). Furthermore, in rat hepatocytes, odanacatib shows outstanding metabolic stability with a 96% recovery of the parent identity.[1] In ovariectomized (OVX) rabbits, odanacatib (ODN) administered orally reduces bone loss in a dose-dependent manner. Additionally, Odanacatib (9 µM/day) significantly raises the bone mineral density (BMD) of the femoral neck (10.8%), the greater trochanter (6.5%), and the proximal femur (7.8%).[3] Long-term administration of Odanacatib preserves the normal biomechanical characteristics of the spine in OVX nonhuman primates while effectively inhibiting bone turnover in estrogen-deficient, skeletally mature rhesus monkeys without lowering osteoclast frequency.[4]
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| Enzyme Assay |
Odanacatib, also known as MK-0822, has been shown to exhibit high selectivity against off-target cathepsin B, L, and S. It is a potent, selective, and neutral inhibitor of cathepsin K (human/rabbit) with an IC50 of 0.2 nM/1 nM. Odanacatib binds to cathepsin K specifically and inhibits its activity. This may reduce bone resorption, improve bone mineral density, and reverse osteoporotic changes.
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| Cell Assay |
In order to evaluate cell survival, 100 nM Odanacatib (ODN) or 7 ×104 differentiated osteoclast (OC) cells/cm2 are reseeded on slices of bovine bone. On days 2, 4, 6, and 12, bone slices are fixed without any media alterations. Samples are stained for both the OC number and TRAP activity.
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| Animal Protocol |
Sixteen eight-month-old female Sprague-Dawley (SD) rats, weighing 385 ± 55 g, are provided with water and soft diet food on an as-needed basis in a temperature-controlled environment featuring regular 12-hour light and dark cycles. Four groups of four rats each are created by randomization: the sham group, the OVX + Veh group, the OVX + ODN-l group, and the OVX + ODN-h group. After implant insertion, OVX + ODN-l and OVX + ODN-h groups receive gavage once daily for eight weeks at concentrations of 1 mL/kg and 6 mL/kg, respectively, of odanacatib (ODN, 5 mg/mL). During the same period, a gavage containing 0.5% sodium carboxymethyl cellulose at a concentration of 6 mL/kg is administered to the OVX + Veh group. Following the administration of gavage, intravenous sodium pentobarbital injections are used to kill the rats in each group. Along with the surrounding bone, the implants are removed and preserved in 10% buffered formalin.
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| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
Tmax of 2-6h. The absolute bioavailabilities observed with 30mg and 50 mg doses are 70% and 30% respectively. When taken with high fat meals the 50mg dose's bioavailability increases to 49% and tmax increases to 10.5h. 16.9% excreted in urine. 74.5% excreted in feces. 100L Total clearance of 0.8L/h. Metabolism / Metabolites The major metabolite is the product of hydroxylation by CYP3A4 and CYP2C8. This metabolite is active but is 25 times less effective at inhibiting cathepsin K than odanacatib. The other metabolites are produced through glutathione conjugation, hydrolysis, dealkylation, glucuronidation, oxidation, and cyclization. Biological Half-Life Apparent half life observed to be 87.3-94.7h. |
| Toxicity/Toxicokinetics |
Protein Binding
97.5% bound to plasma proteins. |
| References | |
| Additional Infomation |
Odanacatib is an inhibiter of cathepsin K which was originally developed be Merck & Co as a new treatment for osteoporosis. The drug made it to phase III trials before abandoned due to increased stroke.
Odanacatib is an inhibitor of cathepsin K with potential anti-osteoporotic activity. Odanacatib selectively binds to and inhibits the activity of cathepsin K, which may result in a reduction in bone resorption, improvement of bone mineral density, and a reversal in osteoporotic changes. Cathepsin K, a tissue-specific cysteine protease that catalyzes degradation of bone matrix proteins such as collagen I/II, elastin, and osteonectin plays an important role in osteoclast function and bone resorption. Drug Indication Investigated for use/treatment in osteoporosis. Treatment of osteoporosis Mechanism of Action Odanacatib inhibits cathepsin K, likely by binding to its active site. Cathepsin K is a cysteine protease enzyme which is secreted by osteoclasts. Cathepsin K is responsible for the breakdown of collagen in the bone matrix as part of bone resorption. The inhibition of this enzyme results in decreased bone resorption without affecting bone deposition resulting in increased bone mineral density. This increased bone mineral density strengthens the bone which leads to fewer fractures in osteoporosis. Pharmacodynamics Increases bone mineral density and reduces risk of fractures in osteoporosis. |
| Molecular Formula |
C25H27F4N3O3S
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| Molecular Weight |
525.56
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| Exact Mass |
525.17
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| Elemental Analysis |
C, 57.13; H, 5.18; F, 14.46; N, 8.00; O, 9.13; S, 6.10
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| CAS # |
603139-19-1
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| Related CAS # |
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| PubChem CID |
10152654
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| Appearance |
white solid powder, m.p. = 223 - 224 oC
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
681.6±55.0 °C at 760 mmHg
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| Flash Point |
366.0±31.5 °C
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| Vapour Pressure |
0.0±2.1 mmHg at 25°C
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| Index of Refraction |
1.563
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| LogP |
2.92
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
36
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| Complexity |
934
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| Defined Atom Stereocenter Count |
2
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| SMILES |
S(C([H])([H])[H])(C1C([H])=C([H])C(=C([H])C=1[H])C1C([H])=C([H])C(=C([H])C=1[H])[C@@]([H])(C(F)(F)F)N([H])[C@@]([H])(C([H])([H])C(C([H])([H])[H])(C([H])([H])[H])F)C(N([H])C1(C#N)C([H])([H])C1([H])[H])=O)(=O)=O
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| InChi Key |
FWIVDMJALNEADT-SFTDATJTSA-N
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| InChi Code |
InChI=1S/C25H27F4N3O3S/c1-23(2,26)14-20(22(33)32-24(15-30)12-13-24)31-21(25(27,28)29)18-6-4-16(5-7-18)17-8-10-19(11-9-17)36(3,34)35/h4-11,20-21,31H,12-14H2,1-3H3,(H,32,33)/t20-,21-/m0/s1
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| Chemical Name |
(2S)-N-(1-cyanocyclopropyl)-4-fluoro-4-methyl-2-[[(1S)-2,2,2-trifluoro-1-[4-(4-methylsulfonylphenyl)phenyl]ethyl]amino]pentanamide
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| Synonyms |
Odanacatib; MK 0822; MK0822; MK-0822
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.76 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 2: 4% DMSO+corn oil: 5 mg/mL (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9027 mL | 9.5137 mL | 19.0273 mL | |
| 5 mM | 0.3805 mL | 1.9027 mL | 3.8055 mL | |
| 10 mM | 0.1903 mL | 0.9514 mL | 1.9027 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT00769418 | Completed | Drug: odanacatib Drug: Comparator: Placebo |
Osteoporosis | Merck Sharp & Dohme LLC | September 2004 | Phase 1 |
| NCT01068262 | Completed | Drug: Odanacatib Drug: Comparator: Placebo |
Osteoporosis | Merck Sharp & Dohme LLC | December 8, 2009 | Phase 1 |
| NCT01512693 | Completed | Drug: MK-0822 | Hepatic Insufficiency | Merck Sharp & Dohme LLC | February 23, 2012 | Phase 1 |
| NCT01512667 | Completed | Drug: MK-0822 | Renal Insufficiency | Merck Sharp & Dohme LLC | January 17, 2012 | Phase 1 |
| NCT00729183 | Completed | Drug: Odanacatib Osteoporosis |
Osteoporosis | Merck Sharp & Dohme LLC | October 2, 2008 | Phase 3 |
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