Atiprimod
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| Formula | C22H44N2 |
| Molar mass | 336.608g·mol−1 |
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Atiprimod(INN,codenamedSK&F106615) is a substance being studied in the treatment of certainmultiple myelomasand other advancedcancers.It may block the growth of tumors and the growth ofblood vesselsfrom surrounding tissue to thetumor.This drug is also being researched as a potential treatment for variousautoimmune diseases.
It was first developed byGlaxoSmithKlineas a potential treatment forrheumatoid arthritis.[1][2][3]
It also had application in the treatment of hyperlipidæmia:[4]
This compound has also been shown to killmantle cell lymphomacellsin vitro.[5]
Mechanism of action[edit]
Atiprimod has been shown to inhibitangiogenesis(growth of blood vessels) in a blood vessel model using chicken eggs. It is thought to inhibit the secretion ofvascular endothelial growth factor(VEGF), a growth factor that promotes angiogenesis.[citation needed]
Chemistry[edit]
Atiprimod is anamphiphiliccompound and acationat neutralpH.
The harbinger for Atipromod was obviouslySpirogermanium[41992-23-8].
The substance is an example of anazaspirane.
Synthesis[edit]
The first part of the synthesis uses protocols that were used forPramiverineand agents includingSIR 117. The second half of the synthesis shares features that are consonant withRS 86
The Johnson–Corey–Chaykovsky reaction on 4-Heptanone [123-19-3] (1) gives 2,2-dipropyloxirane [98560-25-9] (2). Treatment with Boron trifluoride etherate [109-63-7] gave 2-Propylpentanal [18295-59-5] (3). Upon acid treatment with Methyl vinyl ketone [78-94-4] (4) this led to 4,4-Dipropylcyclohex-2-enone [60729-41-1] (5). Catalytic hydrogenation of the enone olefin yielded 4,4-Dipropylcyclohexanone [123018-62-2] (7). The Knoevenagel condensation with ethyl 2-cyanoacetate [1187-46-8] (8) led to Cyano-(4,4-dipropyl-cyclohexylidene)-acetic acid ethyl ester [130065-93-9] (8). Conjugate addition of cyanide anion led to ethyl 2-cyano-2-(1-cyano-4,4-dipropylcyclohexyl)acetate, PC45358714 (9). Acid hydrolysis of both the nitrile groups to acids, saponification of the ester, and decarboxylation of the geminal diacid gave 1-(carboxymethyl)-4,4-dipropylcyclohexane-1-carboxylic acid [130065-94-0] (10). Treatment with acetic anhydride gave 8,8-Dipropyl-2-oxaspiro[4.5]decane-1,3-dione [123018-64-4] (11). Condensation with 3-Diethylaminopropylamine [104-78-9] (12) gave the imide and hence, 2-[3-(diethylamino)propyl]-8,8-dipropyl-2-azaspiro[4.5]decane-1,3-dione, PC15634126 (13). Finally reduction of both carbonyl groups with lithium aluminium hydride completed the synthesis of Atiprimod (14).
References[edit]
- ^Jacobs GS (Spring 2004)."Atiprimod: A New Drug Candidate in Early-Stage Development for Myeloma".Myeloma Today.5(10). International Myeloma Foundation. Archived fromthe originalon 2011-07-18.Retrieved2010-09-30.
- ^abBadger, A. M., Schwartz, D. A., Picker, D. H., Dorman, J. W., Bradley, F. C., Cheeseman, E. N., DiMartino, M. J., Hanna, N., Mirabelli, C. K. (November 1990). "Antiarthritic and supressor cell inducing activity of azaspiranes: structure-function relationships of a novel class of immunomodulatory agents". Journal of Medicinal Chemistry. 33 (11): 2963–2970. doi:10.1021/jm00173a010.
- ^US4963557 idem Alison M. Badger, WO1989002889 (to Callisto Pharmaceuticals Inc).
- ^Alison Mary Badger, WO1994025024 (to SmithKline Beecham Corp).
- ^Wang M, Zhang L, Han X, Yang J, Qian J, Hong S, et al. (June 2007)."Atiprimod inhibits the growth of mantle cell lymphoma in vitro and in vivo and induces apoptosis via activating the mitochondrial pathways".Blood.109(12): 5455–5462.doi:10.1182/blood-2006-12-063958.PMID17317853.
- ^US4963557 idem Alison M. Badger, WO1989002889 (to Callisto Pharmaceuticals Inc).
- ^US 5952365,Dagger RE, Grady CW, "2-[2-(dimethylaminoehtyl]-8,8-diproply-2-azaspiro[4.5]decane dimaleate", issued 4 September 1999, assigned to Anormed Inc.
Further reading[edit]
- Hamasaki M, Hideshima T, Tassone P, et al. (June 2005)."Azaspirane (N-N-diethyl-8,8-dipropyl-2-azaspiro 4.5 decane-2-propanamine) inhibits human multiple myeloma cell growth in the bone marrow milieu in vitro and in vivo".Blood.105(11): 4470–6.doi:10.1182/blood-2004-09-3794.PMC1895034.PMID15705788.
External links[edit]
- Atiprimodentry in the public domain NCI Dictionary of Cancer Terms
This article incorporatespublic domain materialfromDictionary of Cancer Terms.U.S. National Cancer Institute.