View source for Semapimod

{{Drugbox
| IUPAC_name        = N,N'-bis[3,5-bis[N-(diaminomethylideneamino)-C-methylcarbonimidoyl]phenyl] decanediamide tetrahydrochloride
| image             = Semapimod_cs.svg
| image2            = Semapimod_sf.gif
| imagename         = Semapimod
| width = 375
| CAS_number        = 164301-51-3
| CAS_supplemental  = <br />{{CAS|352513-83-8}} (base)
| ATC_prefix        = none
| ATC_suffix        = 
| ATC_supplemental  = 
| PubChem           = 5745214
| DrugBank          = 
| chemical_formula  = 
| C=34 | H=56 | Cl=4 | N=18 | O=2
| molecular_weight  = 890.73984 g/mol
| smiles            = CC(=NN=C(N)N)C1=CC(=CC(=C1)NC(=O)CCCCCCCCC(=O)NC2=CC(=CC(=C2)C(=NN=C(N)N)C)C(=NN=C(N)N)C)C(=NN=C(N)N)C.Cl.Cl.Cl.Cl
| bioavailability   = 
| protein_bound     = 
| metabolism        = 
| elimination_half-life = 
| excretion         = 
| pregnancy_AU      =  <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_US      =  <!-- A / B            / C / D / X -->
| pregnancy_category=  
| legal_AU =  <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled-->
| legal_CA =  <!-- Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_UK =  <!-- GSL, P, POM, CD, or Class A, B, C -->
| legal_US =  <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->
| legal_status      = 
| routes_of_administration =
}}
'''Semapimod''' ([[International Nonproprietary Name|INN]]), formerly known as '''CNI-1493''', is an investigational new drug which has [[anti-inflammatory]]<ref name=bianchi1>{{cite pmid|8529104}}</ref>, anti-[[cytokine]]<ref name=bianchi2>{{cite pmid|8642296}}</ref>, [[immunomodulatory]]<ref>{{cite pmid|9605164}}</ref>, [[antiviral]]<ref>{{cite pmid|15630446}}</ref> and [[antimalarial]]<ref>{{cite pmid|18256853}}</ref> properties.  

==History==
Semapimod was developed at the former Picower Institute for Medical Research, and is now licensed to [http://www.cytokinepharmasciences.com/clinical.php Cytokine PharmaSciences]. In 2000, Cytokine PharmaSciences licensed anti-infective applications of semapimod to Axxima Pharmaceuticals, but Axxima became insolvent in Dec. 2004 and its assets were [http://74.125.95.132/search?q=cache:ej3TeoQcD-gJ:www.gpc-biotech.com/en/news_media/press_releases/2005/03-02-2005.html&cd=4&hl=en&ct=clnk&gl=us acquired by GPC Biotech], which has recently merged into [http://www.agennix.com/attachments/070_021809_PR_Transaction_en.pdf Agennix AG][http://www.agennix.com/index.php?option=com_content&view=article&id=74%3Amerger-of-gpc-biotech-ag-into-agennix-ag-closes&catid=8%3Apress-releases&Itemid=56&lang=en]. Although the disposition of Axxima's partial rights to semapimod was not specified in these merger announcements, Cytokine PharmaSciences does not currently list any licensees for semapimod on its [http://www.cytokinepharmasciences.com/partners.php website].

==Mechanism of action==
Semapimod was first developed to inhibit [[nitric oxide]] synthesis by inflammatory [[macrophages]], via inhibition of the uptake of [[arginine]] which macrophages require for nitric oxide synthesis.<ref name=bianchi1/> Subsequently it was found that suppression of nitric oxide synthesis occurred even at semapimod concentrations 10-fold less than required for inhibition of arginine uptake, suggesting that this molecule was a more general inhibitor of [[Inflammation|inflammatory]] responses.<ref name=bianchi2/>  Further work revealed that semapimod suppressed the [[translation (genetics)|translation]] efficiency of [[tumor necrosis factor]] production.<ref>{{cite pmid|8632999}}</ref>  Specifically, semapimod was found to be an inhibitor of [[p38 kinase|p38 MAP kinase]] activation.<ref>{{cite pmid|9205949}}</ref> Surprisingly, however, the primary mode of action in vivo is now thought to be via stimulation of the vagus nerve, thereby down-regulating inflammatory pathways via the recently discovered cholinergic anti-inflammatory pathway.<ref>{{cite pmid|17273548}}</ref><ref>{{cite pmid|18065685}}</ref>

==Pharmacology and clinical trials==
In a preclinical study in rats, semapimod was found to suppress [[cytokine storm|cytokine-storm]] induction by the anticancer cytokine [[interleukin-2]] (IL-2) without decreasing its anticancer properties, allow larger doses of IL-2 to be administered.<ref>{{cite pmid|9539777}}</ref>  A subsequent phase I trial in humans failed to show an increase in the tolerated dose of IL-2, although indications of pharmacological activity as an inhibitor of tumor necrosis factor production were observed.<ref>{{cite pmid|11297238}}</ref>

In a preliminary clinical trial of semapimod in patients with moderate to severe [[Crohn's disease]], positive clinical changes were observed, including endoscopic improvement, positive responses in some patients not responding to [[infliximab]], healing of fistulae, and indications for tapering of steroids; no significant adverse effects were observed.<ref>{{cite pmid|11781274}}</ref>

In a small clinical trial against post-ERCP [[pancreatitis]], significant suppression was not observed, although investigators observed a significant reduction of the incidence of hyperamylasemia and the levels of post-ERCP amylase.<ref>{{cite pmid|18455169}}</ref>

In the clinical trials above, semapimod tetrahydrochloride was administered by intravenous injection.  This route has drawbacks such as dose-limiting phlebitis.[http://www.lifescience-online.com/CPSI-2364,24761.html]  Recently Cytokine PharmaSciences has announced the development of novel salt forms of semapimod which are said to be orally absorbable; a phase I clinical trial of one of these salt forms, CPSI-2364, has been completed, and a phase II trial is planned for 2010.[http://www.cytokinepharmasciences.com/cpsi-news/NEWS1248095128.pdf][http://www.cytokinepharmasciences.com/clinical.php]

==Chemistry==
Semapimod is synthesized by reacting 3,5-diacetylaniline<ref>{{cite pmid|6690682}}</ref> with [[sebacoyl chloride]] in the presence of [[pyridine]], followed by reaction of the resulting tetraketone with [[aminoguanidine]] hydrochloride.<ref name=bianchi1/>
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