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{{Short description|Chemical compound}} |
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{{Use dmy dates|date= |
{{Use dmy dates|date=June 2023}} |
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{{Drugbox |
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{{Infobox drug |
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| Verifiedfields = changed |
| Verifiedfields = changed |
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| verifiedrevid = 477316280 |
| verifiedrevid = 477316280 |
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| IUPAC_name = 4,5-dimethyl-3-(2-oxo-2-phenylethyl)-thiazolium chloride |
| IUPAC_name = 4,5-dimethyl-3-(2-oxo-2-phenylethyl)-thiazolium chloride |
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| image = Alagebrium_structure.svg |
| image = Alagebrium_structure.svg |
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| image2 = |
| image2 = Alagebrium sf.png |
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<!--Clinical data--> |
<!--Clinical data--> |
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<!--Identifiers--> |
<!--Identifiers--> |
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| CAS_number_Ref = {{cascite| |
| CAS_number_Ref = {{cascite|correct|CAS}} |
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| CAS_number = |
| CAS_number = 393121-34-1 |
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| ATC_prefix = none |
| ATC_prefix = none |
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| PubChem = 216306 |
| PubChem = 216306 |
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| UNII = DGH49JXB1F |
| UNII = DGH49JXB1F |
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| index2_label = as chloride |
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| CAS_number2_Ref = {{cascite|correct|CAS}} |
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| CAS_number2 = 341028-37-3 |
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| UNII2_Ref = {{fdacite|correct|FDA}} |
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| UNII2 = 79QS8K2877 |
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<!--Chemical data--> |
<!--Chemical data--> |
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| C=13 | H=14 | Cl=1 | N=1 | O=1 | S=1 |
| C=13 | H=14 | Cl=1 | N=1 | O=1 | S=1 |
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| molecular_weight = 267.774 g/mol |
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| smiles = [Cl-].O=C(c1ccccc1)C[n+]2c(c(sc2)C)C |
| smiles = [Cl-].O=C(c1ccccc1)C[n+]2c(c(sc2)C)C |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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'''Alagebrium''' (formerly known as '''ALT-711''') was a drug candidate developed by |
'''Alagebrium''' (formerly known as '''ALT-711''', dimethyl-3-N-phenacylthiazolium chloride) was a drug candidate developed by Alteon, Inc. It was the first drug candidate to be clinically tested for the purpose of breaking the crosslinks caused by [[advanced glycation endproduct]]s (AGEs), thereby reversing one of the main mechanisms of aging.<ref name=alteonr&d>{{cite web |title = R&D overview: A.G.E. crosslink breakers and Alagebrium | publisher = Alteon Corporation| url = http://www.alteon.com/overview.htm | access-date = 2007-07-04| archive-url= https://web.archive.org/web/20070701092005/http://www.alteon.com/overview.htm| archive-date= 1 July 2007 | url-status= live}}</ref> Through this effect Alagebrium is designed to reverse the stiffening of blood vessel walls that contributes to [[hypertension]] and [[cardiovascular disease]], as well as many other forms of degradation associated with protein crosslinking.<ref name=alteonr&d2>{{cite web |title = Product Candidate: A.G.E. crosslink breakers | publisher = Alteon Corporation| url = http://www.alteon.com/overview.htm | access-date = 2007-07-04| archive-url= https://web.archive.org/web/20070701092005/http://www.alteon.com/overview.htm| archive-date= 1 July 2007 | url-status= live}}</ref> Alagebrium has proven effective in reducing [[Systole (medicine)|systolic]] [[blood pressure]]<ref>{{cite journal | vauthors = Bakris GL, Bank AJ, Kass DA, Neutel JM, Preston RA, Oparil S | title = Advanced glycation end-product cross-link breakers. A novel approach to cardiovascular pathologies related to the aging process | journal = American Journal of Hypertension | volume = 17 | issue = 12 Pt 2 | pages = 23S–30S | date = December 2004 | pmid = 15607432 | doi = 10.1016/j.amjhyper.2004.08.022 | doi-access = free }}</ref> and providing therapeutic benefit for patients with [[Diastole|diastolic]] [[heart failure]].<ref>{{cite journal | vauthors = Little WC, Zile MR, Kitzman DW, Hundley WG, O'Brien TX, Degroof RC | title = The effect of alagebrium chloride (ALT-711), a novel glucose cross-link breaker, in the treatment of elderly patients with diastolic heart failure | journal = Journal of Cardiac Failure | volume = 11 | issue = 3 | pages = 191–195 | date = April 2005 | pmid = 15812746 | doi = 10.1016/j.cardfail.2004.09.010 }}</ref> |
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==Mechanism== |
==Mechanism== |
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[[Advanced glycation end-product]]s (AGEs) are proteins that become [[Glycation|glycated]] as a result of exposure to sugars.<ref>{{cite journal | vauthors = Goldin A, Beckman JA, Schmidt AM, Creager MA | title = Advanced glycation end products: sparking the development of diabetic vascular injury | journal = Circulation | volume = 114 | issue = 6 | pages = 597–605 | date = August 2006 | pmid = 16894049 | doi = 10.1161/CIRCULATIONAHA.106.621854 | doi-access = free }}</ref> They are a bio-marker implicated in aging and the development, or worsening, of many [[degenerative diseases]], such as [[diabetes]], [[atherosclerosis]], [[chronic kidney disease]], and [[Alzheimer's disease]]. Pharmacologic intervention with alagebrium directly targets the biochemical pathway leading to AGEs. Although alagebrium may break some important AGE crosslinks, there is no evidence that it is effective against the most prevalent crosslink: [[glucosepane]].<ref>{{cite journal | vauthors = Monnier VM, Sell DR | title = Prevention and repair of protein damage by the Maillard reaction in vivo | journal = Rejuvenation Research | volume = 9 | issue = 2 | pages = 264–273 | year = 2006 | pmid = 16706654 | doi = 10.1089/rej.2006.9.264 }}</ref> |
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{{Refimprove section|date=April 2010}} |
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AGEs are structures that form irreversibly when carbohydrates react non-enzymatically with proteins, lipids, or DNA. Many proteins, including structural proteins such as collagen and elastin, play an integral role in the architecture of tissues and organs and maintenance of cardiovascular elasticity and vascular wall integrity. Accumulation of these glycocedic cross-linkages can impair the normal function of organs, thicken arteries, stiffen muscles, or lead to other characteristic declines of [[Senescence|biolological aging]].<ref name=Melton>{{cite journal|last=Melton|first=Lisa|title=AGE Breakers|journal=Scientific American|date=July 2000}}</ref> In addition to this, the formation of AGE crosslinks leads to increased stiffness and loss of function of tissues and organs, and abnormal protein accumulation, which together cause many of the complications of aging and diabetes. Diabetic individuals form excessive amounts of AGEs earlier in life than non-diabetic individuals. AGEs are also known to induce oxidative stress, in which reactive molecules provoke the underlying component of inflammation. |
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Pharmacologic intervention with alagebrium directly targets the biochemical pathway leading to the stiffness of the cardiovascular system. Removal of the AGEs by cleavage of the abnormal crosslinking bonds has been associated with diminished inflammatory and sclerotic signaling pathways. These pathways are responsible for the deposition of abnormal amounts of matrix proteins that physically stiffen tissues. The presence of AGE crosslinks also renders tissues and organs less susceptible to normal turnover thus enhancing the presence of these abnormal bonds on various molecules. Importantly, alagebrium does not disrupt the natural carbohydrate modification to proteins, intra-molecular crosslinking or peptide bonds that are responsible for maintaining the normal integrity of the collagen chain. Thus, normal structure and function is preserved while abnormal crosslinking is reduced.<ref name=Melton/> |
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Although alagebrium may break some important AGE crosslinks, there is no evidence that it is effective against the most prevalent crosslink: [[glucosepane]].<ref>{{cite journal | doi=10.1089/rej.2006.9.264 | vauthors=Monnier VM, Sell DR | title=Prevention and repair of protein damage by the Maillard reaction in vivo | journal=[[Rejuvenation Research]] | volume=9 | issue=2 | year=2006 | pages=264–273 | pmid=16706654 }}</ref> |
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==History== |
==History== |
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Alteon said that it had selected ALT-711 as its lead AGE-breaker based on preclinical results in its annual report for the year 1997 and that it was preparing an IND filing.<ref>{{cite web|title=Alteon 10-K For the fiscal year ended December 31, 1997|url=https://www.sec.gov/Archives/edgar/data/878903/0000893220-98-000631.txt|publisher=Alteon via SEC Edgar|date=31 March 1998}}</ref> |
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The chemical compound had been discovered many years ago, and had traveled a circuitous route through academia, research firms, and finally, Alteon. There are two prominent attributes to Alagebrium (as Alteon renamed it). The first is that it is not a difficult compound to synthesize. An active market arose very quickly after the early Phase I and II tests ended. Independent, lab-tested, certified for purity product was available for a short time on the market at about $3 per gram. |
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The INN name was proposed in 2004<ref>{{cite journal|title=Proposed INN: List 91|journal=WHO Drug Information|date=2004|volume=18|issue=2|url=https://www.who.int/medicines/publications/druginformation/innlists/PL91.pdf?ua=1}}</ref> and recommended in 2005.<ref name=INN>{{cite journal|title=Recommended INN: List 53|journal=WHO Drug Information|date=2005|volume=19|issue=1|url=https://www.who.int/medicines/publications/druginformation/innlists/RL53.pdf?ua=1}}</ref> |
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In 2006 Alteon merged with a company called HaptoGuard that had cash and a potential diagnostic test for [[haptoglobin]]; as part of the merger Genentech, which held preferred shares in Alteon, converted their shares to common ones and received the right to get milestone payments and royalties on sales of alagebrium, and option rights to license ALT-2074.<ref name=10K2007/> In 2007, the company changed its name to Synvista Therapeutics, Inc.<ref name=10K2007>{{cite web|title=10-K For the fiscal year ended December 31, 2007|url=https://www.sec.gov/Archives/edgar/data/878903/000114420408019114/v108414_10k.htm|publisher=U.S. Securities and Exchange Commission|department=Synvista Therapeutics |via=SEC Edgar|date=15 March 2008}}</ref> Synvista announced that it was terminating clinical trials of alagebrium in January 2009 in order to focus on the diagnostic test and another clinical candidate SYI-2074 (formerly ALT-2074).<ref>{{cite news| vauthors = Myers C |title=Synvista Therapeutics Announces Termination of Clinical Trials of Alagebrium and SYI-2074 and Provides Business Update|url=http://www.fiercebiotech.com/biotech/synvista-therapeutics-announces-termination-of-clinical-trials-of-alagebrium-and-syi-2074|work=FierceBiotech|date=29 January 2009|language=en}}</ref> The company seems to have discontinued operations and their website is no longer available. |
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== See also == |
== See also == |
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* [[Advanced glycation end product]] |
* [[Advanced glycation end product]] |
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==References== |
== References == |
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{{Reflist}} |
{{Reflist}} |
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[[Category: |
[[Category:Post-translational modification]] |
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[[Category:Thiazoles]] |
[[Category:Thiazoles]] |
Latest revision as of 23:21, 11 November 2023
Clinical data | |
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ATC code |
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Identifiers | |
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CAS Number |
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PubChem CID | |
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ChEMBL | |
CompTox Dashboard (EPA) | |
ECHA InfoCard | 100.164.267 |
Chemical and physical data | |
Formula | C13H14ClNOS |
Molar mass | 267.77 g·mol−1 |
3D model (JSmol) | |
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(what is this?) (verify) |
Alagebrium (formerly known as ALT-711, dimethyl-3-N-phenacylthiazolium chloride) was a drug candidate developed by Alteon, Inc. It was the first drug candidate to be clinically tested for the purpose of breaking the crosslinks caused by advanced glycation endproducts (AGEs), thereby reversing one of the main mechanisms of aging.[1] Through this effect Alagebrium is designed to reverse the stiffening of blood vessel walls that contributes to hypertension and cardiovascular disease, as well as many other forms of degradation associated with protein crosslinking.[2] Alagebrium has proven effective in reducing systolic blood pressure[3] and providing therapeutic benefit for patients with diastolic heart failure.[4]
Mechanism
Advanced glycation end-products (AGEs) are proteins that become glycated as a result of exposure to sugars.[5] They are a bio-marker implicated in aging and the development, or worsening, of many degenerative diseases, such as diabetes, atherosclerosis, chronic kidney disease, and Alzheimer's disease. Pharmacologic intervention with alagebrium directly targets the biochemical pathway leading to AGEs. Although alagebrium may break some important AGE crosslinks, there is no evidence that it is effective against the most prevalent crosslink: glucosepane.[6]
History
Alteon said that it had selected ALT-711 as its lead AGE-breaker based on preclinical results in its annual report for the year 1997 and that it was preparing an IND filing.[7]
The INN name was proposed in 2004[8] and recommended in 2005.[9]
In 2006 Alteon merged with a company called HaptoGuard that had cash and a potential diagnostic test for haptoglobin; as part of the merger Genentech, which held preferred shares in Alteon, converted their shares to common ones and received the right to get milestone payments and royalties on sales of alagebrium, and option rights to license ALT-2074.[10] In 2007, the company changed its name to Synvista Therapeutics, Inc.[10] Synvista announced that it was terminating clinical trials of alagebrium in January 2009 in order to focus on the diagnostic test and another clinical candidate SYI-2074 (formerly ALT-2074).[11] The company seems to have discontinued operations and their website is no longer available.
See also
References
- ^ "R&D overview: A.G.E. crosslink breakers and Alagebrium". Alteon Corporation. Archived from the original on 1 July 2007. Retrieved 4 July 2007.
- ^ "Product Candidate: A.G.E. crosslink breakers". Alteon Corporation. Archived from the original on 1 July 2007. Retrieved 4 July 2007.
- ^ Bakris GL, Bank AJ, Kass DA, Neutel JM, Preston RA, Oparil S (December 2004). "Advanced glycation end-product cross-link breakers. A novel approach to cardiovascular pathologies related to the aging process". American Journal of Hypertension. 17 (12 Pt 2): 23S–30S. doi:10.1016/j.amjhyper.2004.08.022. PMID 15607432.
- ^ Little WC, Zile MR, Kitzman DW, Hundley WG, O'Brien TX, Degroof RC (April 2005). "The effect of alagebrium chloride (ALT-711), a novel glucose cross-link breaker, in the treatment of elderly patients with diastolic heart failure". Journal of Cardiac Failure. 11 (3): 191–195. doi:10.1016/j.cardfail.2004.09.010. PMID 15812746.
- ^ Goldin A, Beckman JA, Schmidt AM, Creager MA (August 2006). "Advanced glycation end products: sparking the development of diabetic vascular injury". Circulation. 114 (6): 597–605. doi:10.1161/CIRCULATIONAHA.106.621854. PMID 16894049.
- ^ Monnier VM, Sell DR (2006). "Prevention and repair of protein damage by the Maillard reaction in vivo". Rejuvenation Research. 9 (2): 264–273. doi:10.1089/rej.2006.9.264. PMID 16706654.
- ^ "Alteon 10-K For the fiscal year ended December 31, 1997". Alteon via SEC Edgar. 31 March 1998.
- ^ "Proposed INN: List 91" (PDF). WHO Drug Information. 18 (2). 2004.
- ^ "Recommended INN: List 53" (PDF). WHO Drug Information. 19 (1). 2005.
- ^ a b "10-K For the fiscal year ended December 31, 2007". Synvista Therapeutics. U.S. Securities and Exchange Commission. 15 March 2008 – via SEC Edgar.
- ^ Myers C (29 January 2009). "Synvista Therapeutics Announces Termination of Clinical Trials of Alagebrium and SYI-2074 and Provides Business Update". FierceBiotech.