Details
Stereochemistry | ABSOLUTE |
Molecular Formula | C19H26N6O |
Molecular Weight | 354.4493 |
Optical Activity | UNSPECIFIED |
Defined Stereocenters | 1 / 1 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
CC[C@H](CO)NC1=NC2=C(N=CN2C(C)C)C(NCC3=CC=CC=C3)=N1
InChI
InChIKey=BTIHMVBBUGXLCJ-OAHLLOKOSA-N
InChI=1S/C19H26N6O/c1-4-15(11-26)22-19-23-17(20-10-14-8-6-5-7-9-14)16-18(24-19)25(12-21-16)13(2)3/h5-9,12-13,15,26H,4,10-11H2,1-3H3,(H2,20,22,23,24)/t15-/m1/s1
Molecular Formula | C19H26N6O |
Molecular Weight | 354.4493 |
Charge | 0 |
Count |
|
Stereochemistry | ABSOLUTE |
Additional Stereochemistry | No |
Defined Stereocenters | 1 / 1 |
E/Z Centers | 0 |
Optical Activity | UNSPECIFIED |
Seliciclib (CYC202, R-roscovitine) is a second-generation orally available cyclin-dependent kinases (CDKs) inhibitor that competes for ATP binding sites on these kinases. It is a direct inhibitor of cyclin CDK2/E, CDK2/A and it has inhibitory effects on cyclin H/CDK7, CDK5, and CDK9. CDKs are enzymes that are central to the process of cell division and cell cycle control and play pivotal roles in cancer cell growth and DNA damage repair. Seliciclib exerts an anti-proliferative effect via several key mechanisms: selective downregulation of proliferative and survival proteins and upregulation of p53, leading to growth arrest or apoptosis. The second one is decreasing phosphorylation of Rb and modulating E2F transcriptional activity leading to growth arrest or apoptosis. Seliciclib is currently in phase II clinical trial as a drug candidate for the treatment of Cushing's disease and as a potential therapeutic agent for the treatment of cystic fibrosis (CF). In addition, it is in Phase II trials for non-small cell lung cancer and nasopharyngeal carcinoma.
CNS Activity
Originator
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL301 Sources: https://www.ncbi.nlm.nih.gov/pubmed/12432547 |
0.1 µM [IC50] | ||
Target ID: CHEMBL3116 Sources: https://www.ncbi.nlm.nih.gov/pubmed/15958589 |
0.81 µM [IC50] | ||
Target ID: CHEMBL3055 Sources: https://www.ncbi.nlm.nih.gov/pubmed/15958589 |
0.36 µM [IC50] | ||
Target ID: CHEMBL4036 Sources: https://www.ncbi.nlm.nih.gov/pubmed/9030781 |
0.2 µM [IC50] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
Cmax
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
3.76 μg/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/20822897 |
1600 mg single, oral dose: 1600 mg route of administration: Oral experiment type: SINGLE co-administered: |
SELICICLIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
AUC
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
24.73 μg × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/20822897 |
1600 mg single, oral dose: 1600 mg route of administration: Oral experiment type: SINGLE co-administered: |
SELICICLIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
T1/2
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
3.11 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/20822897 |
1600 mg single, oral dose: 1600 mg route of administration: Oral experiment type: SINGLE co-administered: |
SELICICLIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
Doses
Dose | Population | Adverse events |
---|---|---|
1800 mg 2 times / day multiple, oral Highest studied dose Dose: 1800 mg, 2 times / day Route: oral Route: multiple Dose: 1800 mg, 2 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: |
DLT: Hypokalaemia, Asthenia... Dose limiting toxicities: Hypokalaemia (33.3%) Sources: Asthenia (33.3%) |
1250 mg 2 times / day multiple, oral MTD Dose: 1250 mg, 2 times / day Route: oral Route: multiple Dose: 1250 mg, 2 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: |
|
1600 mg 2 times / day multiple, oral MTD Dose: 1600 mg, 2 times / day Route: oral Route: multiple Dose: 1600 mg, 2 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: |
|
1600 mg 2 times / day multiple, oral Studied dose Dose: 1600 mg, 2 times / day Route: oral Route: multiple Dose: 1600 mg, 2 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: |
DLT: Vomiting, Nausea... Dose limiting toxicities: Vomiting (33.3%) Sources: Nausea (33.3%) Asthenia (33.3%) Hypokalaemia (33.3%) |
800 mg 2 times / day multiple, oral Studied dose Dose: 800 mg, 2 times / day Route: oral Route: multiple Dose: 800 mg, 2 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: FASTED Sources: |
DLT: GGT increased, Hyperglycaemia... Dose limiting toxicities: GGT increased (25%) Sources: Hyperglycaemia (8.3%) Glycosuria (8.3%) Fatigue (grade 3, 8.3%) Skin rash (grade 3, 8.3%) Hyponatraemia (grade 3, 8.3%) Hypokalaemia (grade 4, 8.3%) |
AEs
AE | Significance | Dose | Population |
---|---|---|---|
Asthenia | 33.3% DLT |
1800 mg 2 times / day multiple, oral Highest studied dose Dose: 1800 mg, 2 times / day Route: oral Route: multiple Dose: 1800 mg, 2 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: |
Hypokalaemia | 33.3% DLT |
1800 mg 2 times / day multiple, oral Highest studied dose Dose: 1800 mg, 2 times / day Route: oral Route: multiple Dose: 1800 mg, 2 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: |
Asthenia | 33.3% DLT |
1600 mg 2 times / day multiple, oral Studied dose Dose: 1600 mg, 2 times / day Route: oral Route: multiple Dose: 1600 mg, 2 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: |
Hypokalaemia | 33.3% DLT |
1600 mg 2 times / day multiple, oral Studied dose Dose: 1600 mg, 2 times / day Route: oral Route: multiple Dose: 1600 mg, 2 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: |
Nausea | 33.3% DLT |
1600 mg 2 times / day multiple, oral Studied dose Dose: 1600 mg, 2 times / day Route: oral Route: multiple Dose: 1600 mg, 2 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: |
Vomiting | 33.3% DLT |
1600 mg 2 times / day multiple, oral Studied dose Dose: 1600 mg, 2 times / day Route: oral Route: multiple Dose: 1600 mg, 2 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: |
GGT increased | 25% DLT |
800 mg 2 times / day multiple, oral Studied dose Dose: 800 mg, 2 times / day Route: oral Route: multiple Dose: 800 mg, 2 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: FASTED Sources: |
Glycosuria | 8.3% DLT |
800 mg 2 times / day multiple, oral Studied dose Dose: 800 mg, 2 times / day Route: oral Route: multiple Dose: 800 mg, 2 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: FASTED Sources: |
Hyperglycaemia | 8.3% DLT |
800 mg 2 times / day multiple, oral Studied dose Dose: 800 mg, 2 times / day Route: oral Route: multiple Dose: 800 mg, 2 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: FASTED Sources: |
Fatigue | grade 3, 8.3% DLT |
800 mg 2 times / day multiple, oral Studied dose Dose: 800 mg, 2 times / day Route: oral Route: multiple Dose: 800 mg, 2 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: FASTED Sources: |
Hyponatraemia | grade 3, 8.3% DLT |
800 mg 2 times / day multiple, oral Studied dose Dose: 800 mg, 2 times / day Route: oral Route: multiple Dose: 800 mg, 2 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: FASTED Sources: |
Skin rash | grade 3, 8.3% DLT |
800 mg 2 times / day multiple, oral Studied dose Dose: 800 mg, 2 times / day Route: oral Route: multiple Dose: 800 mg, 2 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: FASTED Sources: |
Hypokalaemia | grade 4, 8.3% DLT |
800 mg 2 times / day multiple, oral Studied dose Dose: 800 mg, 2 times / day Route: oral Route: multiple Dose: 800 mg, 2 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: FASTED Sources: |
PubMed
Title | Date | PubMed |
---|---|---|
Programmed cell death protein 4 suppresses CDK1/cdc2 via induction of p21(Waf1/Cip1). | 2004 Dec |
|
P21Cip1 is a critical mediator of the cytotoxic action of thymidylate synthase inhibitors in colorectal carcinoma cells. | 2004 Sep 1 |
|
Antiproliferative activity of olomoucine II, a novel 2,6,9-trisubstituted purine cyclin-dependent kinase inhibitor. | 2005 Aug |
|
Seliciclib (CYC202 or R-roscovitine), a small-molecule cyclin-dependent kinase inhibitor, mediates activity via down-regulation of Mcl-1 in multiple myeloma. | 2005 Aug 1 |
|
Indirubin-3'-monoxime, a derivative of a Chinese antileukemia medicine, inhibits P-TEFb function and HIV-1 replication. | 2005 Dec 2 |
|
Metabolism and pharmacokinetics of the cyclin-dependent kinase inhibitor R-roscovitine in the mouse. | 2005 Jan |
|
Antiviral activity of CYC202 in HIV-1-infected cells. | 2005 Jan 28 |
|
Seliciclib (CYC202, R-Roscovitine) induces cell death in multiple myeloma cells by inhibition of RNA polymerase II-dependent transcription and down-regulation of Mcl-1. | 2005 Jun 15 |
|
p25/Cdk5-mediated retinoblastoma phosphorylation is an early event in neuronal cell death. | 2005 Mar 15 |
|
Improved tumor control through circadian clock induction by Seliciclib, a cyclin-dependent kinase inhibitor. | 2006 Nov 15 |
|
The cyclin-dependent kinase inhibitor seliciclib (R-roscovitine; CYC202) decreases the expression of mitotic control genes and prevents entry into mitosis. | 2007 Dec 15 |
|
Cyclin-dependent kinase inhibitor seliciclib shows in vitro activity in diffuse large B-cell lymphomas. | 2007 Jan |
|
Seliciclib (CYC202; r-roscovitine) in combination with cytotoxic agents in human uterine sarcoma cell lines. | 2007 Jan-Feb |
|
Gateways to clinical trials. | 2007 Jul-Aug |
|
Gateways to clinical trials. | 2007 Jun |
|
Crosstalk among Bcl-2 family members in B-CLL: seliciclib acts via the Mcl-1/Noxa axis and gradual exhaustion of Bcl-2 protection. | 2007 Nov |
|
Antiproliferative effects of sapacitabine (CYC682), a novel 2'-deoxycytidine-derivative, in human cancer cells. | 2007 Sep 3 |
|
Human cytomegalovirus IE1 protein enhances herpes simplex virus type 1-induced syncytial formation in U373MG cells. | 2008 Dec |
|
You never know: Cdk inhibitors as anti-cancer drugs. | 2008 Dec 15 |
|
Metabolism of the trisubstituted purine cyclin-dependent kinase inhibitor seliciclib (R-roscovitine) in vitro and in vivo. | 2008 Mar |
|
Lysine methylation of HIV-1 Tat regulates transcriptional activity of the viral LTR. | 2008 May 22 |
|
Effect of seliciclib (CYC202, R-roscovitine) on lymphocyte alloreactivity and acute kidney allograft rejection in rat. | 2008 May 27 |
|
Molecular therapies for systemic lupus erythematosus: clinical trials and future prospects. | 2009 |
|
Liver circadian clock, a pharmacologic target of cyclin-dependent kinase inhibitor seliciclib. | 2009 Aug |
|
The cyclin-dependent kinase inhibitor 5, 6-dichloro-1-beta-D-ribofuranosylbenzimidazole induces nongenotoxic, DNA replication-independent apoptosis of normal and leukemic cells, regardless of their p53 status. | 2009 Aug 12 |
|
Seliciclib in malignancies. | 2009 Dec |
|
Regulation of HIV-1 transcription in cells of the monocyte-macrophage lineage. | 2009 Dec 23 |
|
Pharmacodynamic effects of seliciclib, an orally administered cell cycle modulator, in undifferentiated nasopharyngeal cancer. | 2009 Feb 15 |
|
Induction of cytotoxicity, apoptosis and cell cycle arrest by 1-t-butyl carbamoyl, 7-methyl-indole-3-ethyl isothiocyanate (NB7M) in nervous system cancer cells. | 2009 Feb 6 |
|
Seliciclib (CYC202, R-roscovitine) enhances the antitumor effect of doxorubicin in vivo in a breast cancer xenograft model. | 2009 Jan 15 |
|
Therapeutic efficacy of seliciclib in combination with ionizing radiation for human nasopharyngeal carcinoma. | 2009 Jun 1 |
|
Development of cell-cycle inhibitors for cancer therapy. | 2009 Mar |
|
Gateways to clinical trials. | 2009 Nov |
|
Cdk2 plays a critical role in hepatocyte cell cycle progression and survival in the setting of cyclin D1 expression in vivo. | 2009 Sep 1 |
|
Phase I evaluation of seliciclib (R-roscovitine), a novel oral cyclin-dependent kinase inhibitor, in patients with advanced malignancies. | 2010 Dec |
|
Healthy clocks, healthy body, healthy mind. | 2010 Jan |
|
Targeting the cyclin E-Cdk-2 complex represses lung cancer growth by triggering anaphase catastrophe. | 2010 Jan 1 |
|
Role of senescence and mitotic catastrophe in cancer therapy. | 2010 Jan 21 |
|
Application of new drugs in chronic lymphocytic leukemia. | 2010 May 10 |
|
Combination of sapacitabine and HDAC inhibitors stimulates cell death in AML and other tumour types. | 2010 Oct 26 |
|
Role of NOXA and its ubiquitination in proteasome inhibitor-induced apoptosis in chronic lymphocytic leukemia cells. | 2010 Sep |
|
Cyclin-dependent kinase activity controls the onset of the HCMV lytic cycle. | 2010 Sep 9 |
|
Pyrazolo[4,3-d]pyrimidine bioisostere of roscovitine: evaluation of a novel selective inhibitor of cyclin-dependent kinases with antiproliferative activity. | 2011 Apr 28 |
|
A bioinformatical and functional approach to identify novel strategies for chemoprevention of colorectal cancer. | 2011 Apr 28 |
|
Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. | 2011 Oct 30 |
|
Use of ATP analogs to inhibit HIV-1 transcription. | 2012 Oct 10 |
|
A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery. | 2013 Apr 15 |
|
Comparative structural and functional studies of 4-(thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile CDK9 inhibitors suggest the basis for isotype selectivity. | 2013 Feb 14 |
|
Synergism of cyclin-dependent kinase inhibitors with camptothecin derivatives in small cell lung cancer cell lines. | 2014 Feb 17 |
|
Aryl hydrocarbon receptor-dependent up-regulation of the heterodimeric amino acid transporter LAT1 (SLC7A5)/CD98hc (SLC3A2) by diesel exhaust particle extract in human bronchial epithelial cells. | 2016 Jan 1 |
Sample Use Guides
In Vivo Use Guide
Sources: https://clinicaltrials.gov/ct2/show/NCT02160730
Cushing Disease: R-roscovitine 400 mg oral administration twice daily for 4 days every week for total of 4 weeks.
cystic fibrosis: 200 or 400 mg roscovitine (8) or placebo (4) once daily for 4 cycles of 7 days (4 days "on" and 3 days "off")
Route of Administration:
Oral
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/12432547
CDK2 inhibitors have been proposed as effective anti-cancer therapeutics. It was shown that CYC202 (R-roscovitine) is a potent inhibitor of recombinant CDK2/cyclin E kinase activity (IC(50) = 0.10 microM) with an average cytotoxic IC(50) of 15.2 microM in a panel of 19 human tumour cell lines, and was also demonstrated selectivity for rapidly proliferating cells over non-proliferating cells. A study of the cell cycle effects of CYC202 in Lovo colorectal carcinoma cells showed that the major effect was not the predicted arrest in one part of the cycle, but rather an induction of cell death from all compartments of the cell cycle.
Substance Class |
Chemical
Created
by
admin
on
Edited
Wed Apr 02 09:07:11 GMT 2025
by
admin
on
Wed Apr 02 09:07:11 GMT 2025
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Record UNII |
0ES1C2KQ94
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Record Status |
Validated (UNII)
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Record Version |
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NCI_THESAURUS |
C2185
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NCI_THESAURUS |
C129825
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8546
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DTXSID20171928
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SUB185009
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C62783
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m9849
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186692-46-6
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160355
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CHEMBL14762
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SELICICLIB
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100000170830
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701554
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DB06195
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