PEN-866

Synopsis, Chemistry

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Also known as: Locnartecan, Hdc sn-38, Pen-866, 1472614-83-7, Sta 12-8666, Sdc-trap 0063

Molecular Formula

C₄₉H₄₉N₇O₉

Molecular Weight

880.0 g/mol

InChI Key

QTPZAEAYDWMVJO-GGCSAXROSA-N

FDA UNII

56DL1J49LR

Locnartecan is a miniature drug conjugate composed of the irinotecan metabolite 7-ethyl-10-hydroxy-camptothecin (SN-38) conjugated, through a cleavable linker, to a ligand of chaperone protein heat shock protein 90 (Hsp90), with potential antineoplastic activity. Upon administration of locnartecan, the HSP90 ligand moiety targets HSP90, which allows the conjugate to penetrate, accumulate and be retained in the tumor cell. Once the linker is cleaved, the SN-38 moiety is released in a sustained manner. SN-38 then binds to and inhibits topoisomerase I by stabilizing the cleavable complex between topoisomerase I and DNA, which results in DNA breaks, inhibition of DNA replication and apoptosis. Compared to SN-38 alone, locnartecan preferentially targets, accumulates and is retained in the tumor cells due to its binding to Hsp90, which results in increased concentrations of SN-38 at the tumor site. This allows sustained release of SN-38 and leads to increased and prolonged efficacy while reducing toxicity to normal, healthy tissues. Hsp90, a chaperone protein upregulated and activated in a variety of tumor cells compared to normal healthy tissue, regulates the folding, stability and degradation of many oncogenic signaling proteins.

1 2D Structure

PEN-866

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

[(19S)-10,19-diethyl-19-hydroxy-14,18-dioxo-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-1(21),2,4(9),5,7,10,15(20)-heptaen-7-yl] 4-[2-[5-[3-(2,4-dihydroxy-5-propan-2-ylphenyl)-5-oxo-1H-1,2,4-triazol-4-yl]indol-1-yl]ethyl]piperidine-1-carboxylate

2.1.2 InChI

InChI=1S/C49H49N7O9/c1-5-31-33-20-30(8-9-38(33)50-43-35(31)24-55-40(43)22-37-36(45(55)59)25-64-46(60)49(37,63)6-2)65-48(62)54-16-12-27(13-17-54)11-15-53-18-14-28-19-29(7-10-39(28)53)56-44(51-52-47(56)61)34-21-32(26(3)4)41(57)23-42(34)58/h7-10,14,18-23,26-27,57-58,63H,5-6,11-13,15-17,24-25H2,1-4H3,(H,52,61)/t49-/m0/s1

2.1.3 InChI Key

QTPZAEAYDWMVJO-GGCSAXROSA-N

2.1.4 Canonical SMILES

CCC1=C2CN3C(=CC4=C(C3=O)COC(=O)C4(CC)O)C2=NC5=C1C=C(C=C5)OC(=O)N6CCC(CC6)CCN7C=CC8=C7C=CC(=C8)N9C(=NNC9=O)C1=CC(=C(C=C1O)O)C(C)C

2.1.5 Isomeric SMILES

CCC1=C2CN3C(=CC4=C(C3=O)COC(=O)[C@@]4(CC)O)C2=NC5=C1C=C(C=C5)OC(=O)N6CCC(CC6)CCN7C=CC8=C7C=CC(=C8)N9C(=NNC9=O)C1=CC(=C(C=C1O)O)C(C)C

2.2 Other Identifiers

2.2.1 UNII

56DL1J49LR

2.3 Synonyms

2.3.1 MeSH Synonyms

1. Sta-12-8666

2. Sta-8666

2.3.2 Depositor-Supplied Synonyms

1. Locnartecan

2. Hdc Sn-38

3. Pen-866

4. 1472614-83-7

5. Sta 12-8666

6. Sdc-trap 0063

7. 56dl1j49lr

8. Hsp90-targeted Sn-38 Conjugate Pen-866

9. [(19s)-10,19-diethyl-19-hydroxy-14,18-dioxo-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-1(21),2,4(9),5,7,10,15(20)-heptaen-7-yl] 4-[2-[5-[3-(2,4-dihydroxy-5-propan-2-ylphenyl)-5-oxo-1h-1,2,4-triazol-4-yl]indol-1-yl]ethyl]piperidine-1-carboxylate

10. Locnartecan [inn]

11. Pen866

12. Chembl4297475

13. Pen-866 [who-dd]

14. Schembl15522240

15. Schembl22223739

16. Sta-8666

17. Sb19799

18. (4s)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1h-pyrano(3',4':6,7)indolizino(1,2-b)quinolin9-yl 4-(2-(5-(3-(2,4-dihydroxy-5-(propan-2-yl)phenyl)-5-oxo-1,5-dihydro-4h-1,2,4-triazol-4-yl)-1h-indol-1-yl)ethyl)piperidine-1-carboxylate

19. 1-piperidinecarboxylic Acid, 4-(2-(5-(3-(2,4-dihydroxy-5-(1-methylethyl)phenyl)-1,5-dihydro-5-oxo-4h-1,2,4-triazol-4-yl)-1h-indol-1-yl)ethyl)-, (4s)-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo-1h-pyrano(3',4':6,7)indolizino(1,2-b)quinolin-9-yl

20. 1-piperidinecarboxylic Acid, 4-(2-(5-(3-(2,4-dihydroxy-5-(1-methylethyl)phenyl)-1,5-dihydro-5-oxo-4h-1,2,4-triazol-4-yl)-1h-indol-1-yl)ethyl)-, (4s)-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo-1h-pyrano(3',4':6,7)indolizino(1,2-b)quinolin-9-yl Ester

2.4 Create Date

2019-01-15

3 Chemical and Physical Properties

Molecular Formula	C₄₉H₄₉N₇O₉
Molecular Weight	880.0 g/mol
XLogP3	5.4
Hydrogen Bond Donor Count	4
Hydrogen Bond Acceptor Count	11
Rotatable Bond Count	10
Exact Mass	879.35917617 g/mol
Monoisotopic Mass	879.35917617 g/mol
Topological Polar Surface Area	199 Å²
Heavy Atom Count	65
Formal Charge	0
Complexity	1980
Isotope Atom Count	0
Defined Atom Stereocenter Count	1
Undefined Atom Stereocenter Count	0
Defined Bond Stereocenter Count	0
Undefined Bond Stereocenter Count	0
Covalently Bonded Unit Count	1