Identification

Name
Odanacatib
Accession Number
DB06670
Type
Small Molecule
Groups
Investigational
Description

Odanacatib is an inhibiter of cathepsin K which was originally developed be Merck & Co as a new treatment for osteoporosis [1]. The drug made it to phase III trials before abandoned due to increased stroke.

Structure
Thumb
Synonyms
Not Available
External IDs
MK-0822 / MK0822
Categories
UNII
N673F6W2VH
CAS number
603139-19-1
Weight
Average: 525.56
Monoisotopic: 525.170925567
Chemical Formula
C25H27F4N3O3S
InChI Key
FWIVDMJALNEADT-SFTDATJTSA-N
InChI
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
IUPAC Name
(2S)-N-(1-cyanocyclopropyl)-4-fluoro-4-methyl-2-{[(1S)-2,2,2-trifluoro-1-{4'-methanesulfonyl-[1,1'-biphenyl]-4-yl}ethyl]amino}pentanamide
SMILES
CC(C)(F)C[C@H](N[C@@H](C1=CC=C(C=C1)C1=CC=C(C=C1)S(C)(=O)=O)C(F)(F)F)C(=O)NC1(CC1)C#N

Pharmacology

Indication

Investigated for use/treatment in osteoporosis [1].

Pharmacodynamics

Increases bone mineral density and reduces risk of fractures in osteoporosis [2].

Mechanism of action

Odanacatib inhibits cathepsin K, likely by binding to its active site [7]. Cathepsin K is a cysteine protease enzyme which is secreted by osteoclasts [5]. 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.

TargetActionsOrganism
UCathepsin K
inhibitor
Human
Absorption

Tmax of 2-6h [2]. 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 [3].

Volume of distribution

100L [3]

Protein binding

97.5% bound to plasma proteins [4].

Metabolism

The major metabolite is the product of hydroxylation by CYP3A4 and CYP2C8 [4]. 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.

Route of elimination

16.9% excreted in urine. 74.5% excreted in feces.

Half life

Apparent half life observed to be 87.3-94.7h [2].

Clearance

Total clearance of 0.8L/h [3].

Toxicity

Odanacatib was found to increase the risk of stroke [1]. No further toxicological studies have been performed.

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AbirateroneThe serum concentration of Odanacatib can be increased when it is combined with Abiraterone.
AcetaminophenThe serum concentration of Odanacatib can be increased when it is combined with Acetaminophen.
Acetyl sulfisoxazoleThe metabolism of Odanacatib can be decreased when combined with Acetyl sulfisoxazole.
AlclometasoneThe metabolism of Alclometasone can be decreased when combined with Odanacatib.
AlfuzosinThe metabolism of Odanacatib can be decreased when combined with Alfuzosin.
AmcinonideThe metabolism of Amcinonide can be decreased when combined with Odanacatib.
AmiodaroneThe serum concentration of Odanacatib can be increased when it is combined with Amiodarone.
AmitriptylineThe metabolism of Amitriptyline can be decreased when combined with Odanacatib.
AmlodipineThe serum concentration of Odanacatib can be increased when it is combined with Amlodipine.
AmsacrineThe serum concentration of Odanacatib can be increased when it is combined with Amsacrine.
Food Interactions
Not Available

References

General References
  1. Mullard A: Merck &Co. drops osteoporosis drug odanacatib. Nat Rev Drug Discov. 2016 Sep 29;15(10):669. doi: 10.1038/nrd.2016.207. [PubMed:27681784]
  2. Anderson MS, Gendrano IN, Liu C, Jeffers S, Mahon C, Mehta A, Mostoller K, Zajic S, Morris D, Lee J, Stoch SA: Odanacatib, a selective cathepsin K inhibitor, demonstrates comparable pharmacodynamics and pharmacokinetics in older men and postmenopausal women. J Clin Endocrinol Metab. 2014 Feb;99(2):552-60. doi: 10.1210/jc.2013-1688. Epub 2013 Nov 25. [PubMed:24276460]
  3. Zajic S, Rossenu S, Hreniuk D, Kesisoglou F, McCrea J, Liu F, Sun L, Witter R, Gauthier D, Helmy R, Joss D, Ni T, Stoltz R, Stone J, Stoch SA: The Absolute Bioavailability and Effect of Food on the Pharmacokinetics of Odanacatib: A Stable-Label i.v./Oral Study in Healthy Postmenopausal Women. Drug Metab Dispos. 2016 Sep;44(9):1450-8. doi: 10.1124/dmd.116.069906. Epub 2016 Jul 11. [PubMed:27402726]
  4. Kassahun K, McIntosh I, Koeplinger K, Sun L, Talaty JE, Miller DL, Dixon R, Zajic S, Stoch SA: Disposition and metabolism of the cathepsin K inhibitor odanacatib in humans. Drug Metab Dispos. 2014 May;42(5):818-27. doi: 10.1124/dmd.113.056580. Epub 2014 Feb 19. [PubMed:24553380]
  5. Boonen S, Rosenberg E, Claessens F, Vanderschueren D, Papapoulos S: Inhibition of cathepsin K for treatment of osteoporosis. Curr Osteoporos Rep. 2012 Mar;10(1):73-9. doi: 10.1007/s11914-011-0085-9. [PubMed:22228398]
  6. Gauthier JY, Chauret N, Cromlish W, Desmarais S, Duong LT, Falgueyret JP, Kimmel DB, Lamontagne S, Leger S, LeRiche T, Li CS, Masse F, McKay DJ, Nicoll-Griffith DA, Oballa RM, Palmer JT, Percival MD, Riendeau D, Robichaud J, Rodan GA, Rodan SB, Seto C, Therien M, Truong VL, Venuti MC, Wesolowski G, Young RN, Zamboni R, Black WC: The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K. Bioorg Med Chem Lett. 2008 Feb 1;18(3):923-8. doi: 10.1016/j.bmcl.2007.12.047. Epub 2008 Jan 15. [PubMed:18226527]
  7. Black WC: Peptidomimetic inhibitors of cathepsin K. Curr Top Med Chem. 2010;10(7):745-51. [PubMed:20337585]
External Links
PubChem Compound
10152654
PubChem Substance
347827781
ChemSpider
8328162
BindingDB
50255753
ChEMBL
CHEMBL481611
Wikipedia
Odanacatib
MSDS
Download (25.4 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentHepatic Insufficiency1
1CompletedTreatmentImpaired Renal Function1
1CompletedTreatmentBone destruction5
1TerminatedTreatmentBone destruction1
2CompletedTreatmentCancer, Breast / Metastatic Bone Disease1
2CompletedTreatmentPostmenopausal Osteoporosis (PMO)1
2CompletedTreatmentBone destruction2
2TerminatedTreatmentOsteoarthritis (OA)1
3CompletedTreatmentPostmenopausal Osteoporosis (PMO)1
3CompletedTreatmentBone destruction2
3TerminatedTreatmentBone destruction1
3WithdrawnPreventionCancer, Breast1
3WithdrawnPreventionProstate Cancer1
3WithdrawnTreatmentBone destruction / Postmenopausal Osteoporosis (PMO)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00666 mg/mLALOGPS
logP4.04ALOGPS
logP3.33ChemAxon
logS-4.9ALOGPS
pKa (Strongest Acidic)11.12ChemAxon
pKa (Strongest Basic)3.25ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area99.06 Å2ChemAxon
Rotatable Bond Count10ChemAxon
Refractivity126.95 m3·mol-1ChemAxon
Polarizability50.35 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as leucine and derivatives. These are compounds containing leucine or a derivative thereof resulting from reaction of leucine at the amino group or the carboxy group, or from the replacement of any hydrogen of glycine by a heteroatom.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
Leucine and derivatives
Alternative Parents
Biphenyls and derivatives / Alpha amino acid amides / Benzenesulfonyl compounds / Aralkylamines / N-acyl amines / Sulfones / Secondary carboxylic acid amides / Nitriles / Dialkylamines / Organopnictogen compounds
show 5 more
Substituents
Leucine or derivatives / Alpha-amino acid amide / Biphenyl / Benzenesulfonyl group / Aralkylamine / Monocyclic benzene moiety / Fatty amide / N-acyl-amine / Fatty acyl / Benzenoid
show 23 more
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Proteoglycan binding
Specific Function
Closely involved in osteoclastic bone resorption and may participate partially in the disorder of bone remodeling. Displays potent endoprotease activity against fibrinogen at acid pH. May play an i...
Gene Name
CTSK
Uniprot ID
P43235
Uniprot Name
Cathepsin K
Molecular Weight
36965.82 Da
References
  1. Gauthier JY, Chauret N, Cromlish W, Desmarais S, Duong LT, Falgueyret JP, Kimmel DB, Lamontagne S, Leger S, LeRiche T, Li CS, Masse F, McKay DJ, Nicoll-Griffith DA, Oballa RM, Palmer JT, Percival MD, Riendeau D, Robichaud J, Rodan GA, Rodan SB, Seto C, Therien M, Truong VL, Venuti MC, Wesolowski G, Young RN, Zamboni R, Black WC: The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K. Bioorg Med Chem Lett. 2008 Feb 1;18(3):923-8. doi: 10.1016/j.bmcl.2007.12.047. Epub 2008 Jan 15. [PubMed:18226527]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Kassahun K, McIntosh I, Koeplinger K, Sun L, Talaty JE, Miller DL, Dixon R, Zajic S, Stoch SA: Disposition and metabolism of the cathepsin K inhibitor odanacatib in humans. Drug Metab Dispos. 2014 May;42(5):818-27. doi: 10.1124/dmd.113.056580. Epub 2014 Feb 19. [PubMed:24553380]
  2. Marcantonio EE, Ballard J, Gibson CR, Kassahun K, Palamanda J, Tang C, Evers R, Liu C, Zajic S, Mahon C, Mostoller K, Hreniuk D, Mehta A, Morris D, Wagner JA, Stoch SA: Prednisone has no effect on the pharmacokinetics of CYP3A4 metabolized drugs - midazolam and odanacatib. J Clin Pharmacol. 2014 Nov;54(11):1280-9. doi: 10.1002/jcph.338. Epub 2014 Jun 25. [PubMed:24895078]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
  1. Kassahun K, McIntosh I, Koeplinger K, Sun L, Talaty JE, Miller DL, Dixon R, Zajic S, Stoch SA: Disposition and metabolism of the cathepsin K inhibitor odanacatib in humans. Drug Metab Dispos. 2014 May;42(5):818-27. doi: 10.1124/dmd.113.056580. Epub 2014 Feb 19. [PubMed:24553380]

Carriers

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. Kassahun K, McIntosh I, Koeplinger K, Sun L, Talaty JE, Miller DL, Dixon R, Zajic S, Stoch SA: Disposition and metabolism of the cathepsin K inhibitor odanacatib in humans. Drug Metab Dispos. 2014 May;42(5):818-27. doi: 10.1124/dmd.113.056580. Epub 2014 Feb 19. [PubMed:24553380]

Drug created on March 19, 2008 10:47 / Updated on September 21, 2018 09:43