Varespladib methyl: Difference between revisions
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Revision as of 03:56, 10 September 2011
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| Other names | A-002 |
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| Routes of administration | Oral |
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| Formula | C22H22N2O5 |
| Molar mass | 394.4 g·mol−1 |
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Varespladib methyl (also known as A-002, formerly LY333013 and S-3013) is a secretory phospholipase A2 (sPLA2) inhibitor under development by Anthera Pharmaceuticals as a treatment for acute coronary syndrome (ACS).[1] Varespladib methyl is an orally bioavailable prodrug of the molecule varespladib.[2] It is currently under active investigation in a Phase III clinical trial called VISTA-16.[3]
Mechanism
Increased levels of sPLA2 have been observed in patients with cardiovascular disease, and may lead to both acute and chronic disease manifestations by promoting vascular inflammation. Plasma levels of sPLA2 can predict coronary events in patients who recently suffered an ACS as well as in those with stable coronary artery disease.[4][5]
Furthermore, sPLA2 remodels lipoproteins, notably low-density lipoproteins (LDL) and their receptors, which are responsible for removing cholesterol from the body. This remodeling can lead to increased deposition of LDL and cholesterol in the artery wall. In combination with chronic vascular inflammation, these deposits lead to atherosclerosis.[6]
Varespladib inhibits the IIA, V and X isoforms of sPLA2 to reduce inflammation, lower and modulate lipid levels, and reduce levels of C-reactive protein (CRP) and interleukin-6 (IL-6), both indicators of inflammation.[1][7]
Clinical Development
Varespladib methyl was originally developed jointly by Eli Lilly and Company and Shionogi & Co., Ltd., and was acquired by Anthera Pharmaceuticals in 2005.[8]
A Phase II study by Anthera successfully demonstrated selective sPLA2 inhibition as well as statistically significant anti-inflammatory responses and reductions in LDL cholesterol levels.[9] Two other Phase II trials, conducted in patients with coronary artery disease, found significant decreases in sPLA2 and LDL cholesterol levels, as well as CRP and other inflammatory biomarkers.[7][10][11] Varespladib methyl has also been shown to further reduce LDL and inflammatory biomarker levels when administered in conjunction with a cholesterol lowering statin therapy.[12]
In 2010, a Phase III study entitled VISTA-16 was launched to evaluate the safety and efficacy of short-term treatment with varespladib methyl in subjects with ACS.[13][14]
References
- ^ a b "A-002: Short Term (16 week) Treatment of Acute Coronary Syndrome". Anthera Pharmaceuticals, Inc. Retrieved 2011-8-17.
{{cite web}}: Check date values in:|accessdate=(help) - ^ Fraser, H., Hislop, C., Christie, R.M., Rick, H.L., Reidy, C.A., Chouinard, M.L., Eacho, P.I., Gould, K.E., Trias, J. (2009). "Varespladib (A-002), a secretory phospholipase A2 inhibitor, reduces atherosclerosis and aneurysm formation in ApoE-/- mice". Journal of Cardiovascular Pharmacology. 53 (1): 60–5. doi:10.1097/FJC.0b013e318195bfbc. PMID 19129734.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ "Anthera Pharmaceuticals Reports 2011 First Quarter Financial Results and Operational Update" (Press release). Anthera Pharmaceuticals, Inc. 29 July 2010.
- ^ Mallat, Z., Steg, G., Benessiano, J., Tanguy, M., Fox, K.A., Collet, J., Dabbous, O.H., Henry, P., Carruthers, K.F., Dauphin, A., Arguelles, C.S., Masliah, J., Hugel, B., Montalescot, G., Freyssinet, J., Asselian, B., Tedgui, A. (2005). "Circulating Secretory Phospholipase A2 Activity Predicts Recurrent Events in Patients With Severe Acute Coronary Syndromes". Journal of the American College of Cardiology. 46 (7): 1249–57. doi:10.1016/j.jacc.2005.06.056. PMID 16198839.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Kugiyama, K., Ota, Y., Takazoe, K., Moriyama, Y., Kawano, H., Miyao, Y., Sakamoto, T., Soejima, H., Ogawa, H., Doi, H., Sugiyama, S., Yasue, H. (1999). "Circulating Levels of Secretory Type II Phospholipase A2 Predict Coronary Events in Patients with Coronary Artery Disease". Circulation. 100 (12): 1280–4. doi:10.1161/01.CIR.100.12.1280. PMID 10491371.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Mallat, Z., Lambeau, G., Tedgui, A. (201o). "Lipoprotein-Associated and Secreted Phospholipases A2 in Cardiovascular Disease: Roles as Biological Effectors and Biomarkers". Circulation. 122 (21): 2183–200. doi:10.1161/CIRCULATIONAHA.110.936393. PMID 21098459.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ a b Rosenson, R.S., Elliott, M., Stasiv, Y., Hislop, C. (2011). "Randomized trial of an inhibitor of secretory phospholipase A2 on atherogenic lipoprotein subclasses in statin-treated patients with coronary heart disease". European Heart Journal. 32 (8): 999–1005. doi:10.1093/eurheartj/ehq374. PMID 21081550.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ "Anthera Licenses Portfolio of Anti-Inflammatory Products From Eli Lilly and Company and Shionogi & Co., Ltd" (Press release). Anthera Pharmaceuticals, Inc. 6 September 2006.
- ^ "Anthera's Varespladib Meets Primary Endpoint In Phase 2 Francis Trial For The Treatment Of Acute Coronary Syndrome" (Press release). Anthera Pharmaceuticals, Inc. 6 May 2009.
- ^ Rosenson R.S., Hislop C., McConnell D., Elliott M, Stasiv Y, Wang N, Waters D.D. (2009). "Effects of 1-H-indole-3-glyoxamide (A 002) on concentration of secretory phospholipase A2 (PLASMA study): a phase II double-blind, randomized, placebo-controlled trial". The Lancet. 373 (9664): 649–58. doi:10.1016/S0140-6736(09)60403-7. PMID 19231633.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Rosenson, R.S., Fraser, H., Trias, J., Hislop, C. (2010). "Varespladib methyl in cardiovascular disease". Expert Opinions in Investigational Drugs. 19 (10): 1245–55. PMID 20809869.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Rosenson, R.S., Hislop, C., Elliott, M., Stasiv, Y., Goulder, M., Waters, D. (2010). "Effects of varespladib methyl on biomarkers and major cardiovascular events in acute coronary syndrome patients". Journal of American College of Cardiology. 56 (14): 1079–88. doi:10.1016/j.jacc.2010.06.015. PMID 20863951.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ "Anthera Enrolls First Patients in Pivotal Varespladib Phase 3 Clinical Study" (Press release). Anthera Pharmaceuticals, Inc. 23 June 2010.
- ^ ClinicalTrials.gov. "VISTA-16 Trial: Evaluation of Safety and Efficacy of Short-term A-002 Treatment in Subjects With Acute Coronary Syndrome". United States National Institute of Health. Retrieved 2011-8-17.
{{cite web}}: Check date values in:|accessdate=(help)