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Details

Stereochemistry ABSOLUTE
Molecular Formula C53H84NO14P
Molecular Weight 990.2061
Optical Activity UNSPECIFIED
Defined Stereocenters 15 / 15
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of RIDAFOROLIMUS

SMILES

[H][C@@]12CC[C@@H](C)[C@@](O)(O1)C(=O)C(=O)N3CCCC[C@@]3([H])C(=O)O[C@@]([H])(CC(=O)[C@H](C)\C=C(C)\[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)\C=C\C=C\C=C(C)\[C@H](C2)OC)[C@H](C)C[C@@H]4CC[C@@H](OP(C)(C)=O)[C@@H](C4)OC

InChI

InChIKey=BUROJSBIWGDYCN-GAUTUEMISA-N
InChI=1S/C53H84NO14P/c1-32-18-14-13-15-19-33(2)44(63-8)30-40-23-21-38(7)53(61,67-40)50(58)51(59)54-25-17-16-20-41(54)52(60)66-45(35(4)28-39-22-24-43(46(29-39)64-9)68-69(11,12)62)31-42(55)34(3)27-37(6)48(57)49(65-10)47(56)36(5)26-32/h13-15,18-19,27,32,34-36,38-41,43-46,48-49,57,61H,16-17,20-26,28-31H2,1-12H3/b15-13+,18-14+,33-19+,37-27+/t32-,34-,35-,36-,38-,39+,40+,41+,43-,44+,45+,46-,48-,49+,53-/m1/s1

HIDE SMILES / InChI

Molecular Formula C53H84NO14P
Molecular Weight 990.2061
Charge 0
Count
MOL RATIO 1 MOL RATIO (average)
Stereochemistry ABSOLUTE
Additional Stereochemistry No
Defined Stereocenters 15 / 15
E/Z Centers 0
Optical Activity UNSPECIFIED

Description

Ridaforolimus (Deforolimus, MK-8669) is an investigational oral mTOR inhibitor in development for the treatment of metastatic soft-tissue or bone sarcomas. Ridaforolimus is being co-developed by Merck and ARIAD Pharmaceuticals. Ridaforolimus (Deforolimus, MK-8669) is a selective mTOR inhibitor with IC50 of 0.2 nM in HT-1080 cell line; while not classified as a prodrug, mTOR inhibition and FKBP12 binding is similar to rapamycin. mTOR is a protein kinase that controls cell growth by regulating many cellular processes, including protein synthesis and autophagy. Compared with other mTOR inhibitors, ridaforolimus is not a prodrug and has shown in vivo stability. Both intravenous and oral formulations of the compound are being tested in clinical trials for the treatment of various solid tumors and hematologic malignancies. The initial indication is soft-tissue and bone sarcomas. Ridaforolimus was indicated to treat patients with metastatic soft tissue sarcoma or bone sarcoma whose disease has not progressed after at least 4 cycles of chemotherapy. In June 2012, Merck & Co., Inc. announced the receipt of a Complete Response Letter from the U.S. Food and Drug Administration (FDA), advising the company that the New Drug Application (NDA) for ridaforolimus had not been approved. Currently Ridaforolimus is in phase III clinical trials for the treatment of Coronary artery restenosis.

CNS Activity

Originator

Approval Year

Targets

Primary TargetPharmacologyConditionPotency
0.2 nM [IC50]

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Unknown
Primary
Unknown

Cmax

ValueDoseCo-administeredAnalytePopulation
101.19 ng/mL
30 mg single, oral
RIDAFOROLIMUS plasma
Homo sapiens
82.66 ng/mL
30 mg 1 times / day steady-state, oral
RIDAFOROLIMUS plasma
Homo sapiens
139 ng/mL
22 mg 1 times / day steady-state, oral
RIDAFOROLIMUS plasma
Homo sapiens
228 ng/mL
28 mg 1 times / day steady-state, oral
RIDAFOROLIMUS plasma
Homo sapiens
200 ng/mL
33 mg 1 times / day steady-state, oral
RIDAFOROLIMUS plasma
Homo sapiens
55.2 ng/mL
10 mg 1 times / day steady-state, oral
RIDAFOROLIMUS plasma
Homo sapiens
105 ng/mL
10 mg 1 times / day steady-state, oral
RIDAFOROLIMUS plasma
Homo sapiens

AUC

ValueDoseCo-administeredAnalytePopulation
853.68 ng × h/mL
30 mg single, oral
RIDAFOROLIMUS plasma
Homo sapiens
735.42 ng × h/mL
30 mg 1 times / day steady-state, oral
RIDAFOROLIMUS plasma
Homo sapiens
1340 ng × h/mL
22 mg 1 times / day steady-state, oral
RIDAFOROLIMUS plasma
Homo sapiens
2330 ng × h/mL
28 mg 1 times / day steady-state, oral
RIDAFOROLIMUS plasma
Homo sapiens
2280 ng × h/mL
33 mg 1 times / day steady-state, oral
RIDAFOROLIMUS plasma
Homo sapiens
696 ng × h/mL
10 mg 1 times / day steady-state, oral
RIDAFOROLIMUS plasma
Homo sapiens
1858 ng × h/mL
10 mg 1 times / day steady-state, oral
RIDAFOROLIMUS plasma
Homo sapiens

T1/2

ValueDoseCo-administeredAnalytePopulation
25.5 h
22 mg 1 times / day steady-state, oral
RIDAFOROLIMUS plasma
Homo sapiens
28.2 h
28 mg 1 times / day steady-state, oral
RIDAFOROLIMUS plasma
Homo sapiens
26.9 h
33 mg 1 times / day steady-state, oral
RIDAFOROLIMUS plasma
Homo sapiens
33.6 h
10 mg 1 times / day steady-state, oral
RIDAFOROLIMUS plasma
Homo sapiens
58.4 h
10 mg 1 times / day steady-state, oral
RIDAFOROLIMUS plasma
Homo sapiens

PubMed

Sample Use Guides

In Vivo Use Guide
40 mg po 5 days/week
Route of Administration: Oral
In Vitro Use Guide
Treatment of HT-1080 cells with Deforolimus induces a dose-dependent inhibition of phosphorylation of both S6 and 4E-BP1, with IC50 of 0.2 nM and 5.6 nM, respectively, and leads to a decrease in cell size, an increase in the proportion of cells in the G1 phase of the cell cycle, and inhibition of glucose uptake. Deforolimus displays significant antiproliferative activity a broad panel of cell lines with EC50 of 0.2-2.3 nM.
Substance Class Chemical
Record UNII
48Z35KB15K
Record Status Validated (UNII)
Record Version