Darapladib
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MedKoo CAT#: 319502

CAS#: 356057-34-6

Description: Darapladib, also known as SB-480848, is a reversible lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor with IC50 of 0.25 nM, which is in Phase 3 trials. Recent studies showed that risk of major coronary events not reduced by darapladib therapy. In patients with stable coronary heart disease, darapladib did not significantly reduce the risk of the primary composite end point of cardiovascular death, myocardial infarction, or stroke.

Chemical Structure

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Darapladib
CAS# 356057-34-6
Product data Instruction

Theoretical Analysis

MedKoo Cat#: 319502
Name: Darapladib
CAS#: 356057-34-6
Chemical Formula: C36H38F4N4O2S
Exact Mass: 666.27
Molecular Weight: 666.780
Elemental Analysis: C, 64.85; H, 5.74; F, 11.40; N, 8.40; O, 4.80; S, 4.81

Price and Availability

Size Price Availability Quantity
5mg USD 295
10mg USD 450
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Synonym: SB-480848; SB 480848; SB480848; Darapladib.

IUPAC/Chemical Name: N-[2-(diethylamino)ethyl]-2-[[(4-fluorophenyl)methyl]thio]-4,5,6,7-tetrahydro-4-oxo-N-[[4'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]methyl]-1H-Cyclopentapyrimidine-1-acetamide

InChi Key: WDPFJWLDPVQCAJ-UHFFFAOYSA-N

InChi Code: InChI=1S/C36H38F4N4O2S/c1-3-42(4-2)20-21-43(22-25-8-12-27(13-9-25)28-14-16-29(17-15-28)36(38,39)40)33(45)23-44-32-7-5-6-31(32)34(46)41-35(44)47-24-26-10-18-30(37)19-11-26/h8-19H,3-7,20-24H2,1-2H3

SMILES Code: O=C(N(CCN(CC)CC)CC1=CC=C(C2=CC=C(C(F)(F)F)C=C2)C=C1)CN(C3=C4CCC3)C(SCC5=CC=C(F)C=C5)=NC4=O

Appearance: Solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

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Product Data:
Product Data
Instruction:
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Biological target: Darapladib is a potent inhibitor of lipoprotein-associated phospholipase A2 (Lp-PLA2) with IC50 of 0.25 nM.
In vitro activity: In this study, we evaluated the anti-glioma effects of darapladib, a selective reversible inhibitor of lipoprotein-associated phospholipase A2 (Lp-PLA2) that is encoded by the PLA2G7 gene and serves as a predictive biomarker of sub-clinical inflammation in cardiovascular diseases. The three glioma cell lines (rat C6 glioma cell line, human U87MG, and human U251MG) and an ex vivo brain tissue slice-glioma cell co-culture system were used to validate the inhibitory effect of darapladib on the expansion of glioma cells. Exposure to darapladib at doses higher than 5 μM induced profound cytotoxicity in C6, U87MG, and U251MG. Moreover, the colony formation ability of the glioma cell lines was significantly repressed after the addition of darapladib. Although darapladib did not reduce the generation of the Lp-PLA2 downstream molecule, arachidonic acid (AA), in the glioma cells, this small compound triggered mitochondrial membrane depolarization and cell apoptosis in these glioma cells. In addition, transient exposure to darapladib induced the upregulation of phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2) levels, but reduced phosphorylation of AKT/PKB (protein kinase B). Reference: Toxicol Appl Pharmacol. 2020 Sep 1;402:115133. https://pubmed.ncbi.nlm.nih.gov/32668280/
In vivo activity: The principal aim of this study was to examine whether darapladib (a selective Lp-PLA2 inhibitor) could reduce the elevated LpPLA2 and Rho kinase activity in atherosclerosis. Studies were performed in male Sprague-Dawley rats. The atherosclerosis rats were prepared by feeding them with a high-cholesterol diet for 10 weeks. Levels of TC, LDL-C, CRP, Lp-PLA2, and Rho kinase activity were respectively reduced in darapladib groups, whereas NO production was enhanced. When compared to the low-dose darapladib group, the reduction of the levels of TC, LDL-C, CRP, and Lp-PLA2 was more prominent in the high-dose darapladib group (p<0.05), and the increase of NO production was more prominent (p<0.05). Cardiomyocyte apoptosis of the high-dose darapladib group was also significantly reduced compared to the low-dose darapladib group (p<0.05). However, there was no significant difference in Rho kinase activity between the low-dose darapladib group and the high-dose darapladib group (p>0.05). In conclusion, darapladib, a LpPLA2 inhibitor, leads to cardiovascular protection that might be mediated by its inhibition of both Rho kinase and Lp-PLA2 in atherosclerosis. Reference: Yonsei Med J. 2016 Mar;57(2):321-7. https://pubmed.ncbi.nlm.nih.gov/26847282/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 72.0 107.98
Ethanol 62.0 92.98

Preparing Stock Solutions

The following data is based on the product molecular weight 666.78 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Zhang J, Xu DL, Liu XB, Bi SJ, Zhao T, Sui SJ, Ji XP, Lu QH. Darapladib, a Lipoprotein-Associated Phospholipase A2 Inhibitor, Reduces Rho Kinase Activity in Atherosclerosis. Yonsei Med J. 2016 Mar;57(2):321-7. doi: 10.3349/ymj.2016.57.2.321. PMID: 26847282; PMCID: PMC4740522. 2. Wihastuti TA, Heriansyah T, Hanifa H, Andarini S, Sholichah Z, Sulfia YH, Adam AA, Refialdinata J, Lutfiana NC. Darapladib inhibits atherosclerosis development in type 2 diabetes mellitus Sprague-Dawley rat model. Endocr Regul. 2018 Apr 1;52(2):69-75. doi: 10.2478/enr-2018-0008. PMID: 29715185. 3. Wang YJ, Chang SB, Wang CY, Huang HT, Tzeng SF. The selective lipoprotein-associated phospholipase A2 inhibitor darapladib triggers irreversible actions on glioma cell apoptosis and mitochondrial dysfunction. Toxicol Appl Pharmacol. 2020 Sep 1;402:115133. doi: 10.1016/j.taap.2020.115133. Epub 2020 Jul 12. PMID: 32668280.
In vitro protocol: 1. Wang YJ, Chang SB, Wang CY, Huang HT, Tzeng SF. The selective lipoprotein-associated phospholipase A2 inhibitor darapladib triggers irreversible actions on glioma cell apoptosis and mitochondrial dysfunction. Toxicol Appl Pharmacol. 2020 Sep 1;402:115133. doi: 10.1016/j.taap.2020.115133. Epub 2020 Jul 12. PMID: 32668280.
In vivo protocol: 1. Zhang J, Xu DL, Liu XB, Bi SJ, Zhao T, Sui SJ, Ji XP, Lu QH. Darapladib, a Lipoprotein-Associated Phospholipase A2 Inhibitor, Reduces Rho Kinase Activity in Atherosclerosis. Yonsei Med J. 2016 Mar;57(2):321-7. doi: 10.3349/ymj.2016.57.2.321. PMID: 26847282; PMCID: PMC4740522. 2. Wihastuti TA, Heriansyah T, Hanifa H, Andarini S, Sholichah Z, Sulfia YH, Adam AA, Refialdinata J, Lutfiana NC. Darapladib inhibits atherosclerosis development in type 2 diabetes mellitus Sprague-Dawley rat model. Endocr Regul. 2018 Apr 1;52(2):69-75. doi: 10.2478/enr-2018-0008. PMID: 29715185.

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1: Hu C, Tompson D, Magee M, Chen Q, Liu YM, Zhu W, Zhao H, Gross AS, Liu Y. Single and Multiple Dose Pharmacokinetics, Pharmacodynamics and Safety of the Novel Lipoprotein-Associated Phospholipase A2 Enzyme Inhibitor Darapladib in Healthy Chinese Subjects: An Open Label Phase-1 Clinical Trial. PLoS One. 2015 Oct 14;10(10):e0139862. doi: 10.1371/journal.pone.0139862. eCollection 2015. PubMed PMID: 26465780; PubMed Central PMCID: PMC4605839.

2: He Magee M, Shaddinger B, Collins D, Siddiqi S, Soffer J. The pharmacokinetics and safety of darapladib in subjects with severe renal impairment. Br J Clin Pharmacol. 2015 Oct;80(4):654-61. doi: 10.1111/bcp.12661. Epub 2015 Jul 6. PubMed PMID: 25953363; PubMed Central PMCID: PMC4594701.

3: Staurenghi G, Ye L, Magee MH, Danis RP, Wurzelmann J, Adamson P, McLaughlin MM; Darapladib DME Study Group. Darapladib, a lipoprotein-associated phospholipase A2 inhibitor, in diabetic macular edema: a 3-month placebo-controlled study. Ophthalmology. 2015 May;122(5):990-6. doi: 10.1016/j.ophtha.2014.12.014. Epub 2015 Mar 5. PubMed PMID: 25749297.

4: Campos CM, Suwannasom P, Koenig W, Serruys PW, Garcia-Garcia HM. Darapladib for the treatment of cardiovascular disease. Expert Rev Cardiovasc Ther. 2015 Jan;13(1):33-48. doi: 10.1586/14779072.2015.986466. Review. PubMed PMID: 25521799.

5: Duarte JH. Acute coronary syndromes: Risk of major coronary events not reduced by darapladib therapy. Nat Rev Cardiol. 2014 Nov;11(11):621. doi: 10.1038/nrcardio.2014.148. Epub 2014 Sep 16. PubMed PMID: 25223450.

6: O'Donoghue ML, Braunwald E, White HD, Lukas MA, Tarka E, Steg PG, Hochman JS, Bode C, Maggioni AP, Im K, Shannon JB, Davies RY, Murphy SA, Crugnale SE, Wiviott SD, Bonaca MP, Watson DF, Weaver WD, Serruys PW, Cannon CP; SOLID-TIMI 52 Investigators, Steen DL. Effect of darapladib on major coronary events after an acute coronary syndrome: the SOLID-TIMI 52 randomized clinical trial. JAMA. 2014 Sep 10;312(10):1006-15. doi: 10.1001/jama.2014.11061. Erratum in: JAMA. 2014 Oct 8;312(14):1473. Dylan P. Steen[corrected to Dylan L. Steen]. PubMed PMID: 25173516.

7: Mullard A. GSK's darapladib failures dim hopes for anti-inflammatory heart drugs. Nat Rev Drug Discov. 2014 Jul;13(7):481-2. doi: 10.1038/nrd4381. PubMed PMID: 24981346.

8: Magee MH, Shearn S, Shaddinger B, Fang Z, Glaser R. An effect of moderate hepatic impairment on the pharmacokinetics and safety of darapladib. Br J Clin Pharmacol. 2014 Nov;78(5):1014-21. doi: 10.1111/bcp.12436. PubMed PMID: 24938621; PubMed Central PMCID: PMC4243875.

9: Roberts A. Coronary artery disease: Darapladib fails to improve the STABILITY of CAD. Nat Rev Cardiol. 2014 Jun;11(6):310. doi: 10.1038/nrcardio.2014.50. Epub 2014 Apr 15. PubMed PMID: 24736761.

10: STABILITY Investigators, White HD, Held C, Stewart R, Tarka E, Brown R, Davies RY, Budaj A, Harrington RA, Steg PG, Ardissino D, Armstrong PW, Avezum A, Aylward PE, Bryce A, Chen H, Chen MF, Corbalan R, Dalby AJ, Danchin N, De Winter RJ, Denchev S, Diaz R, Elisaf M, Flather MD, Goudev AR, Granger CB, Grinfeld L, Hochman JS, Husted S, Kim HS, Koenig W, Linhart A, Lonn E, López-Sendón J, Manolis AJ, Mohler ER 3rd, Nicolau JC, Pais P, Parkhomenko A, Pedersen TR, Pella D, Ramos-Corrales MA, Ruda M, Sereg M, Siddique S, Sinnaeve P, Smith P, Sritara P, Swart HP, Sy RG, Teramoto T, Tse HF, Watson D, Weaver WD, Weiss R, Viigimaa M, Vinereanu D, Zhu J, Cannon CP, Wallentin L. Darapladib for preventing ischemic events in stable coronary heart disease. N Engl J Med. 2014 May 1;370(18):1702-11. doi: 10.1056/NEJMoa1315878. Epub 2014 Mar 30. PubMed PMID: 24678955.

11: Johnson JL, Shi Y, Snipes R, Janmohamed S, Rolfe TE, Davis B, Postle A, Macphee CH. Effect of darapladib treatment on endarterectomy carotid plaque lipoprotein-associated phospholipase A2 activity: a randomized, controlled trial. PLoS One. 2014 Feb 20;9(2):e89034. doi: 10.1371/journal.pone.0089034. eCollection 2014. PubMed PMID: 24586490; PubMed Central PMCID: PMC3930668.

12: Dave M, Nash M, Young GC, Ellens H, Magee MH, Roberts AD, Taylor MA, Greenhill RW, Boyle GW. Disposition and metabolism of darapladib, a lipoprotein-associated phospholipase A2 inhibitor, in humans. Drug Metab Dispos. 2014 Mar;42(3):415-30. doi: 10.1124/dmd.113.054486. Epub 2013 Dec 30. PubMed PMID: 24378325.

13: Wang K, Xu W, Zhang W, Mo M, Wang Y, Shen J. Triazole derivatives: a series of Darapladib analogues as orally active Lp-PLA2 inhibitors. Bioorg Med Chem Lett. 2013 May 15;23(10):2897-901. doi: 10.1016/j.bmcl.2013.03.062. Epub 2013 Mar 26. PubMed PMID: 23575276.

14: Daida H, Iwase T, Yagi S, Ando H, Nakajima H. Effect of darapladib on plasma lipoprotein-associated phospholipase A2 activity in Japanese dyslipidemic patients, with exploratory analysis of a PLA2G7 gene polymorphism of Val279Phe. Circ J. 2013;77(6):1518-25. Epub 2013 Feb 23. PubMed PMID: 23439604.

15: Acharya NK, Levin EC, Clifford PM, Han M, Tourtellotte R, Chamberlain D, Pollaro M, Coretti NJ, Kosciuk MC, Nagele EP, Demarshall C, Freeman T, Shi Y, Guan C, Macphee CH, Wilensky RL, Nagele RG. Diabetes and hypercholesterolemia increase blood-brain barrier permeability and brain amyloid deposition: beneficial effects of the LpPLA2 inhibitor darapladib. J Alzheimers Dis. 2013;35(1):179-98. doi: 10.3233/JAD-122254. PubMed PMID: 23388174.

16: Koch M, Wiese M. Gene expression signatures of angiocidin and darapladib treatment connect to therapy options in cervical cancer. J Cancer Res Clin Oncol. 2013 Feb;139(2):259-67. doi: 10.1007/s00432-012-1317-9. Epub 2012 Oct 9. PubMed PMID: 23052694.

17: García-García HM, Oemrawsingh RM, Brugaletta S, Vranckx P, Shannon J, Davies R, Boersma E, Serruys PW. Darapladib effect on circulating high sensitive troponin in patients with acute coronary syndromes. Atherosclerosis. 2012 Nov;225(1):142-7. doi: 10.1016/j.atherosclerosis.2012.06.064. Epub 2012 Aug 5. PubMed PMID: 22963982.

18: O'Donoghue ML, Braunwald E, White HD, Serruys P, Steg PG, Hochman J, Maggioni AP, Bode C, Weaver D, Johnson JL, Cicconetti G, Lukas MA, Tarka E, Cannon CP. Study design and rationale for the Stabilization of pLaques usIng Darapladib-Thrombolysis in Myocardial Infarction (SOLID-TIMI 52) trial in patients after an acute coronary syndrome. Am Heart J. 2011 Oct;162(4):613-619.e1. doi: 10.1016/j.ahj.2011.07.018. Epub 2011 Sep 15. PubMed PMID: 21982651.

19: Berger JS, Ballantyne CM, Davidson MH, Johnson JL, Tarka EA, Lawrence D, Trivedi T, Zalewski A, Mohler ER 3rd. Peripheral artery disease, biomarkers, and darapladib. Am Heart J. 2011 May;161(5):972-8. doi: 10.1016/j.ahj.2011.01.017. PubMed PMID: 21570531; PubMed Central PMCID: PMC3750980.

20: White H, Held C, Stewart R, Watson D, Harrington R, Budaj A, Steg PG, Cannon CP, Krug-Gourley S, Wittes J, Trivedi T, Tarka E, Wallentin L. Study design and rationale for the clinical outcomes of the STABILITY Trial (STabilization of Atherosclerotic plaque By Initiation of darapLadIb TherapY) comparing darapladib versus placebo in patients with coronary heart disease. Am Heart J. 2010 Oct;160(4):655-61. doi: 10.1016/j.ahj.2010.07.006. PubMed PMID: 20934559.