U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

Details

Stereochemistry ACHIRAL
Molecular Formula C7H7ClO6P2S.2Na
Molecular Weight 362.572
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of TILUDRONATE DISODIUM

SMILES

[Na+].[Na+].OP([O-])(=O)C(SC1=CC=C(Cl)C=C1)P(O)([O-])=O

InChI

InChIKey=SKUHWSDHMJMHIW-UHFFFAOYSA-L
InChI=1S/C7H9ClO6P2S.2Na/c8-5-1-3-6(4-2-5)17-7(15(9,10)11)16(12,13)14;;/h1-4,7H,(H2,9,10,11)(H2,12,13,14);;/q;2*+1/p-2

HIDE SMILES / InChI

Molecular Formula C7H7ClO6P2S
Molecular Weight 316.592
Charge -2
Count
Stereochemistry RACEMIC
Additional Stereochemistry No
Defined Stereocenters 0 / 1
E/Z Centers 0
Optical Activity ( + / - )

Molecular Formula Na
Molecular Weight 22.9898
Charge 1
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

Tiludronic acid is a bisphosphonate characterized by a (4-chlorophenylthio) group on the carbon atom of the basic P-C-P structure common to all bisphosphonates. Tiludronate is a first generation (non-nitrogenous) bisphosphonate in the same family as etidronate and clodronate. Tiludronate affects calcium metabolism and inhibits bone resorption and soft tissue calcification. Of the tiludronate that is resorbed (from oral preparation) or infused (for intravenous drugs), about 50% is excreted unchanged by the kidney. The remainder has a very high affinity for bone tissue, and is rapidly absorbed onto the bone surface. Tiludronic acid is marketed under the tradename Skelid. In vitro studies indicate that tiludronate disodium acts primarily on bone through a mechanism that involves inhibition of osteoclastic activity with a probable reduction in the enzymatic and transport processes that lead to resorption of the mineralized matrix. Bone resorption occurs following recruitment, activation, and polarization of osteoclasts. Tiludronate disodium appears to inhibit osteoclasts through at least two mechanisms: disruption of the cytoskeletal ring structure, possibly by inhibition of protein-tyrosine-phosphatase, thus leading to detachment of osteoclasts from the bone surface and the inhibition of the osteoclastic proton pump. SKELID is indicated for treatment of Paget's disease of bone (osteitis deformans).

Approval Year

TargetsConditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
SKELID

Approved Use

SKELID is indicated for treatment of Paget's disease of bone (osteitis deformans).

Launch Date

1997
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
1.1 mg/L
200 mg 1 times / day multiple, oral
dose: 200 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
TILUDRONIC ACID plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
2.3 mg/L
400 mg 1 times / day multiple, oral
dose: 400 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
TILUDRONIC ACID plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
4.7 mg/L
600 mg 1 times / day multiple, oral
dose: 600 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
TILUDRONIC ACID plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
7.8 mg/L
800 mg 1 times / day multiple, oral
dose: 800 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
TILUDRONIC ACID plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
10.3 mg × h/L
200 mg 1 times / day multiple, oral
dose: 200 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
TILUDRONIC ACID plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
25 mg × h/L
400 mg 1 times / day multiple, oral
dose: 400 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
TILUDRONIC ACID plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
46.8 mg × h/L
600 mg 1 times / day multiple, oral
dose: 600 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
TILUDRONIC ACID plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
80 mg × h/L
800 mg 1 times / day multiple, oral
dose: 800 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
TILUDRONIC ACID plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
78 h
400 mg 1 times / day multiple, oral
dose: 400 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
TILUDRONIC ACID plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
65.7 h
600 mg 1 times / day multiple, oral
dose: 600 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
TILUDRONIC ACID plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
72 h
800 mg 1 times / day multiple, oral
dose: 800 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
TILUDRONIC ACID plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
Doses

Doses

DosePopulationAdverse events​
800 mg 1 times / day steady, oral
Studied dose
Dose: 800 mg, 1 times / day
Route: oral
Route: steady
Dose: 800 mg, 1 times / day
Sources:
healthy, 18 - 45 years
n = 10
Health Status: healthy
Age Group: 18 - 45 years
Sex: M
Population Size: 10
Sources:
1200 mg 1 times / day steady, oral
Higher than recommended
Dose: 1200 mg, 1 times / day
Route: oral
Route: steady
Dose: 1200 mg, 1 times / day
Sources:
unhealthy, 57 - 87 years
n = 6
Health Status: unhealthy
Condition: Paget's disease of bone
Age Group: 57 - 87 years
Sex: M+F
Population Size: 6
Sources:
Other AEs: Gastrointestinal disturbance...
Other AEs:
Gastrointestinal disturbance (3 patients)
Sources:
600 mg 1 times / day steady, oral
Studied dose
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources:
unhealthy, 68 years
n = 28
Health Status: unhealthy
Condition: Paget's disease of bone
Age Group: 68 years
Sex: M+F
Population Size: 28
Sources:
DLT: Gastrointestinal symptom NOS...
Other AEs: Nausea, Diarrhoea...
Dose limiting toxicities:
Gastrointestinal symptom NOS (75%)
Other AEs:
Nausea (7 patients)
Diarrhoea (7 patients)
Arthralgia (2 patients)
Dyspepsia (5 patients)
Skeletal pain (3 patients)
Vomiting (6 patients)
Sources:
400 mg 1 times / day steady, oral
Recommended
Dose: 400 mg, 1 times / day
Route: oral
Route: steady
Dose: 400 mg, 1 times / day
Sources:
unhealthy, 72 years
n = 29
Health Status: unhealthy
Condition: Paget's disease of bone
Age Group: 72 years
Sex: M+F
Population Size: 29
Sources:
DLT: Gastrointestinal symptom NOS...
Dose limiting toxicities:
Gastrointestinal symptom NOS (31%)
Sources:
AEs

AEs

AESignificanceDosePopulation
Gastrointestinal disturbance 3 patients
1200 mg 1 times / day steady, oral
Higher than recommended
Dose: 1200 mg, 1 times / day
Route: oral
Route: steady
Dose: 1200 mg, 1 times / day
Sources:
unhealthy, 57 - 87 years
n = 6
Health Status: unhealthy
Condition: Paget's disease of bone
Age Group: 57 - 87 years
Sex: M+F
Population Size: 6
Sources:
Arthralgia 2 patients
600 mg 1 times / day steady, oral
Studied dose
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources:
unhealthy, 68 years
n = 28
Health Status: unhealthy
Condition: Paget's disease of bone
Age Group: 68 years
Sex: M+F
Population Size: 28
Sources:
Skeletal pain 3 patients
600 mg 1 times / day steady, oral
Studied dose
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources:
unhealthy, 68 years
n = 28
Health Status: unhealthy
Condition: Paget's disease of bone
Age Group: 68 years
Sex: M+F
Population Size: 28
Sources:
Dyspepsia 5 patients
600 mg 1 times / day steady, oral
Studied dose
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources:
unhealthy, 68 years
n = 28
Health Status: unhealthy
Condition: Paget's disease of bone
Age Group: 68 years
Sex: M+F
Population Size: 28
Sources:
Vomiting 6 patients
600 mg 1 times / day steady, oral
Studied dose
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources:
unhealthy, 68 years
n = 28
Health Status: unhealthy
Condition: Paget's disease of bone
Age Group: 68 years
Sex: M+F
Population Size: 28
Sources:
Diarrhoea 7 patients
600 mg 1 times / day steady, oral
Studied dose
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources:
unhealthy, 68 years
n = 28
Health Status: unhealthy
Condition: Paget's disease of bone
Age Group: 68 years
Sex: M+F
Population Size: 28
Sources:
Nausea 7 patients
600 mg 1 times / day steady, oral
Studied dose
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources:
unhealthy, 68 years
n = 28
Health Status: unhealthy
Condition: Paget's disease of bone
Age Group: 68 years
Sex: M+F
Population Size: 28
Sources:
Gastrointestinal symptom NOS 75%
DLT, Disc. AE
600 mg 1 times / day steady, oral
Studied dose
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources:
unhealthy, 68 years
n = 28
Health Status: unhealthy
Condition: Paget's disease of bone
Age Group: 68 years
Sex: M+F
Population Size: 28
Sources:
Gastrointestinal symptom NOS 31%
DLT, Disc. AE
400 mg 1 times / day steady, oral
Recommended
Dose: 400 mg, 1 times / day
Route: oral
Route: steady
Dose: 400 mg, 1 times / day
Sources:
unhealthy, 72 years
n = 29
Health Status: unhealthy
Condition: Paget's disease of bone
Age Group: 72 years
Sex: M+F
Population Size: 29
Sources:
PubMed

PubMed

TitleDatePubMed
Biological and clinical assessment of a new bisphosphonate, (chloro-4 phenyl) thiomethylene bisphosphonate, in the treatment of Paget's disease of bone.
1988
Intermittent cyclic tiludronate in the treatment of osteoporosis.
2001
Consensus statement on the modern therapy of Paget's disease of bone from a Western Osteoporosis Alliance symposium. Biannual Foothills Meeting on Osteoporosis, Calgary, Alberta, Canada, September 9-10, 2000.
2001 Apr
Treatment of osteoporosis with bisphosphonates.
2001 Feb
Drugs in development: bisphosphonates and metalloproteinase inhibitors.
2003
[Possible mechanism of the specific action of bisphosphonates on osteoclasts].
2003 Feb
[Paget's disease and its therapeutic management].
2005 Apr 23
Prediction of genotoxicity of chemical compounds by statistical learning methods.
2005 Jun
Tiludronate inhibits prostaglandin F2alpha-induced vascular endothelial growth factor synthesis in osteoblasts.
2005 May 31
Management of age-related osteoporosis and prevention of associated fractures.
2006 Sep
Use of zoledronic acid in the treatment of Paget's disease.
2007 Oct
Determination of bisphosphonate active pharmaceutical ingredients in pharmaceuticals and biological material: a review of analytical methods.
2008 Nov 4
Paget disease of bone: therapeutic options.
2008 Oct
Once-yearly zoledronic acid in hip fracture prevention.
2009
Paget's disease 2: exploring diagnosis, management and support strategies.
2009 Feb 24-Mar 2
Arylamino methylene bisphosphonate derivatives as bone seeking matrix metalloproteinase inhibitors.
2013 Nov 1
Patents

Sample Use Guides

A single 400-mg daily oral dose of SKELID (Tiludronic acid), taken with 6 to 8 ounces of plain water only, should be administered for a period of 3 months. Beverages other than plain water (including mineral water), food (see below), and some medications. Patients should not lie down for at least 30 minutes after taking this medication. SKELID should not be taken within 2 hours of food.
Route of Administration: Oral
In Vitro Use Guide
The ability of tiludronate to inhibit proton transport was 5-fold higher in kidney-derived chicken vesicles (IC50 = 1.1 mM) and 10,000-fold higher in vesicles derived from chicken osteoclasts (IC50 = 466 nM). Tiludronate also potently inhibited proton transport in yeast microsomal preparations (IC50 = 3.5 uM) and inhibited the activity of purified yeast V-ATPase.
Substance Class Chemical
Created
by admin
on Sat Dec 16 05:11:18 GMT 2023
Edited
by admin
on Sat Dec 16 05:11:18 GMT 2023
Record UNII
BH6M93CIA0
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
TILUDRONATE DISODIUM
MART.   ORANGE BOOK   USAN   VANDF  
USAN  
Official Name English
TILUDRONIC ACID DISODIUM SALT
MI  
Common Name English
TILUDRONATE SODIUM
WHO-DD  
Common Name English
SR-41319B
Code English
TILUDRONATE DISODIUM [ORANGE BOOK]
Common Name English
TILUDRONATE DISODIUM ANHYDROUS
Common Name English
TILUDRONATE DISODIUM [GREEN BOOK]
Common Name English
TILUDRONATE DISODIUM [VANDF]
Common Name English
SKELID
Brand Name English
TILUDRONATE DISODIUM [MART.]
Common Name English
TILUDRONATE DISODIUM [USAN]
Common Name English
SR 41319B
Code English
TILUDRONIC ACID DISODIUM SALT [MI]
Common Name English
Tiludronate sodium [WHO-DD]
Common Name English
PHOSPHONIC ACID, (((4-CHLOROPHENYL)THIO)METHYLENE)BIS-, DISODIUM SALT
Common Name English
DISODIUM DIHYDROGEN (((P-CHLOROPHENYL)THIO)METHYLENE)DIPHOSPHONATE
Common Name English
Classification Tree Code System Code
NCI_THESAURUS C67439
Created by admin on Sat Dec 16 05:11:18 GMT 2023 , Edited by admin on Sat Dec 16 05:11:18 GMT 2023
NCI_THESAURUS C443
Created by admin on Sat Dec 16 05:11:18 GMT 2023 , Edited by admin on Sat Dec 16 05:11:18 GMT 2023
Code System Code Type Description
EVMPD
SUB04873MIG
Created by admin on Sat Dec 16 05:11:18 GMT 2023 , Edited by admin on Sat Dec 16 05:11:18 GMT 2023
PRIMARY
SMS_ID
100000128701
Created by admin on Sat Dec 16 05:11:18 GMT 2023 , Edited by admin on Sat Dec 16 05:11:18 GMT 2023
PRIMARY
MERCK INDEX
m10868
Created by admin on Sat Dec 16 05:11:18 GMT 2023 , Edited by admin on Sat Dec 16 05:11:18 GMT 2023
PRIMARY Merck Index
ChEMBL
CHEMBL1350
Created by admin on Sat Dec 16 05:11:18 GMT 2023 , Edited by admin on Sat Dec 16 05:11:18 GMT 2023
PRIMARY
NCI_THESAURUS
C61973
Created by admin on Sat Dec 16 05:11:18 GMT 2023 , Edited by admin on Sat Dec 16 05:11:18 GMT 2023
PRIMARY
EVMPD
SUB36102
Created by admin on Sat Dec 16 05:11:18 GMT 2023 , Edited by admin on Sat Dec 16 05:11:18 GMT 2023
PRIMARY
USAN
GG-14
Created by admin on Sat Dec 16 05:11:18 GMT 2023 , Edited by admin on Sat Dec 16 05:11:18 GMT 2023
PRIMARY
PUBCHEM
60936
Created by admin on Sat Dec 16 05:11:18 GMT 2023 , Edited by admin on Sat Dec 16 05:11:18 GMT 2023
PRIMARY
EPA CompTox
DTXSID1048621
Created by admin on Sat Dec 16 05:11:18 GMT 2023 , Edited by admin on Sat Dec 16 05:11:18 GMT 2023
PRIMARY
DRUG BANK
DBSALT000411
Created by admin on Sat Dec 16 05:11:18 GMT 2023 , Edited by admin on Sat Dec 16 05:11:18 GMT 2023
PRIMARY
RXCUI
83153
Created by admin on Sat Dec 16 05:11:18 GMT 2023 , Edited by admin on Sat Dec 16 05:11:18 GMT 2023
PRIMARY RxNorm
FDA UNII
BH6M93CIA0
Created by admin on Sat Dec 16 05:11:18 GMT 2023 , Edited by admin on Sat Dec 16 05:11:18 GMT 2023
PRIMARY
CAS
149845-07-8
Created by admin on Sat Dec 16 05:11:18 GMT 2023 , Edited by admin on Sat Dec 16 05:11:18 GMT 2023
PRIMARY
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PARENT -> SALT/SOLVATE
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