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Details

Stereochemistry ACHIRAL
Molecular Formula 2C7H7ClO6P2S.4Na.H2O
Molecular Weight 743.159
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of TILUDRONATE DISODIUM HEMIHYDRATE

SMILES

O.[Na+].[Na+].[Na+].[Na+].OP([O-])(=O)C(SC1=CC=C(Cl)C=C1)P(O)([O-])=O.OP([O-])(=O)C(SC2=CC=C(Cl)C=C2)P(O)([O-])=O

InChI

InChIKey=KDVKAYPVWJFARG-UHFFFAOYSA-J
InChI=1S/2C7H9ClO6P2S.4Na.H2O/c2*8-5-1-3-6(4-2-5)17-7(15(9,10)11)16(12,13)14;;;;;/h2*1-4,7H,(H2,9,10,11)(H2,12,13,14);;;;;1H2/q;;4*+1;/p-4

HIDE SMILES / InChI

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

Molecular Formula C7H9ClO6P2S
Molecular Weight 318.608
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

Molecular Formula HO
Molecular Weight 17.0073
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
A possible mechanism of the specific action of bisphosphonates on osteoclasts: tiludronate preferentially affects polarized osteoclasts having ruffled borders.
1995 Aug
Tiludronate as a new therapeutic agent in the treatment of navicular disease: a double-blind placebo-controlled clinical trial.
2003 Jun
Management of Paget's disease of bone.
2004 Aug
Steroid-free medium discloses oestrogenic effects of the bisphosphonate clodronate on breast cancer cells.
2004 Nov 1
In vitro toxicity of bisphosphonates on human neuroblastoma cell lines.
2004 Sep
Non-isomerized C-telopeptide fragments are highly sensitive markers for monitoring disease activity and treatment efficacy in Paget's disease of bone.
2005 Apr
[Paget's disease and its therapeutic management].
2005 Apr 23
Prediction of genotoxicity of chemical compounds by statistical learning methods.
2005 Jun
Comparative effects of antiresorptive agents on bone mineral density and bone turnover in postmenopausal women.
2006
Management of age-related osteoporosis and prevention of associated fractures.
2006 Sep
Efficacy of tiludronate in the treatment of horses with signs of pain associated with osteoarthritic lesions of the thoracolumbar vertebral column.
2007 Mar
Treatment with tiludronate has a similar effect to risedronate on Paget's disease activity assessed by bone markers and bone scintigraphy.
2007 Mar-Apr
Pharmacological effects of tiludronate in horses after long-term immobilization.
2007 Sep
Optimizing dosing frequencies for bisphosphonates in the management of postmenopausal osteoporosis: patient considerations.
2008
Comparative pharmacokinetics of two intravenous administration regimens of tiludronate in healthy adult horses and effects on the bone resorption marker CTX-1.
2008 Apr
Treatment of Paget's disease of bone: a survey of clinical practice in Australia.
2008 Jun
Bisphosphonates: molecular mechanisms of action and effects on bone cells, monocytes and macrophages.
2010
Long-term treatment with bisphosphonates and their safety in postmenopausal osteoporosis.
2010 Jul 21
Five-year follow-up of Japanese patients with Paget's disease of the bone after treatment with low-dose oral alendronate: a case series.
2010 May 31
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 11:13:00 GMT 2023
Edited
by admin
on Sat Dec 16 11:13:00 GMT 2023
Record UNII
39SMX0W5WK
Record Status Validated (UNII)
Record Version
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Name Type Language
TILUDRONATE DISODIUM HEMIHYDRATE
Common Name English
TILUDRONIC ACID DISODIUM SALT HEMIHYDRATE [MI]
Common Name English
P,P'-(((4-CHLOROPHENYL)THIO)METHYLENE)BISPHOSPHONIC ACID, DISODIUM HEMIHYDRATE
Systematic Name English
PHOSPHONIC ACID, (((4-CHLOROPHENYL)THIO)METHYLENE)BIS-, DISODIUM SALT, HYDRATE (2:1)
Systematic Name English
Code System Code Type Description
CAS
155453-10-4
Created by admin on Sat Dec 16 11:13:01 GMT 2023 , Edited by admin on Sat Dec 16 11:13:01 GMT 2023
PRIMARY
PUBCHEM
72941702
Created by admin on Sat Dec 16 11:13:01 GMT 2023 , Edited by admin on Sat Dec 16 11:13:01 GMT 2023
PRIMARY
MERCK INDEX
m10868
Created by admin on Sat Dec 16 11:13:01 GMT 2023 , Edited by admin on Sat Dec 16 11:13:01 GMT 2023
PRIMARY
FDA UNII
39SMX0W5WK
Created by admin on Sat Dec 16 11:13:01 GMT 2023 , Edited by admin on Sat Dec 16 11:13:01 GMT 2023
PRIMARY
Related Record Type Details
ANHYDROUS->SOLVATE