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Semapimod cs.svg

Semapimod Mesylate

CPSI-2364,  AXD-455,  CN-1493, CNI 1493

CAS No. 352513-83-8(Semapimod base)

Cas 164301-51-3   4x HCl

 CAS 872830-80-3 (Semapimod mesylate)

MW 1129

CROHNS DISEASE, PHASE 1

N,N’-bis[3,5-bis[(E)-N-(diaminomethylideneamino)-C-methylcarbonimidoyl]phenyl]decanediamide

Decanediamide, N,N’-bis[3,5-bis[1-[(aminoiminomethyl)hydrazono]ethyl]phenyl]-, methanesulfonate

N,N’-Bis(3,5-bis(1-(carbamimidoylhydrazono)ethyl)phenyl)decanediamide

 

A nitric oxide synthesis inhibitor and a p38 MAPK inhibitor potentially for the treatment of Crohn’s disease.

 Semapimod, a small molecule known to inhibit proinflammatory cytokine activity, was studied to determine the optimal dose necessary to achieve a response in patients with moderate to severe Crohn’s disease (CD).

Crohn’s disease (CD) is a chronic inflammatory disease involving the upper and lower gastrointestinal tract and characterized by abdominal pain, weight loss, gastrointestinal bleeding and formation of fistulas between loops of bowel and from the bowel to the skin or other organs. Current therapy for active Crohn’s disease consists of symptomatic treatment, nutritional therapy, salicylates and immunosuppressants or surgical management.

Tumor necrosis factor a (TNF-a) plays a central role in the initiation and amplification of the granulomatous inflammatory reaction seen in CD (van Deventer, 1997). Increased TNF-a is present in gut mucosa as well as in stool of patients with active CD (Braegger et al, 1992). CNI-1493 is a synthetic guanylhydrazone compound that is an inhibitor of TNF-a synthesis. A monoclonal antibody to TNF, infliximab, is now approved for treatment of CD, but not all patients respond and many who do respond eventually become refractory to this treatment as well.

CNI-1493 is a synthetic compound which blocks the production of several inflammatory cytokines, including TNF. Because it blocks production of multiple inflammatory mediators, it may be more active than products targeted to a specific cytokine. In addition, as it is not a biologic, it should not cause hypersensitivity reactions or induce formation of antibodies.

The purpose of this trial is to determine if CNI-1493 is safe and effective in treating patients with moderate to severe Crohn’s Disease in a placebo controlled setting………https://clinicaltrials.gov/ct2/show/NCT00038766

Semapimod (INN), formerly known as CNI-1493, is an investigational new drug which has anti-inflammatory,[1] anti-cytokine,[2] immunomodulatory,[3] antiviral[4] and antimalarial[5] properties.

History

Semapimod was developed at the former Picower Institute for Medical Research, and is now licensed to 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 acquired by GPC Biotech, which has recently merged into Agennix AG[1]. 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 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.[1] 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 inflammatory responses.[2] Further work revealed that semapimod suppressed the translation efficiency of tumor necrosis factor production.[6] Specifically, semapimod was found to be an inhibitor of p38 MAP kinase activation.[7] 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.[8][9]

Pharmacology and clinical trials

In a preclinical study in rats, semapimod was found to suppress 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.[10] 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.[11]

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.[12]

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.[13]

In the clinical trials above, semapimod tetrahydrochloride was administered by intravenous injection. This route has drawbacks such as dose-limiting phlebitis.[2] 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.[3][4]

Chemistry

Semapimod is synthesized by reacting 3,5-diacetylaniline[14] with sebacoyl chloride in the presence of pyridine, followed by reaction of the resulting tetraketone with aminoguanidine hydrochloride.[1]

PATENT

 

  • N,N′-bis(3,5-diacetylphenyl) decanediamide tetrakis (amidinohydrazone) tetrahydrochloride (CNI-1493), which has the following structural formula:

 

SYNTHESIS

The reaction of decanedioyl dichloride (I) with 3,5-diacetylaniline (II) by means of pyridine in dichloromethane gives the corresponding diamide (III), which is condensed with aminoguanidine (IV) in refluxing aqueous ethanol to afford the target tetrakis amidinohydrazone.  EP 0746312; EP 1160240; US 5599984; WO 9519767

http://www.google.com/patents/EP0746312A1?cl=en

References

 

 

 

Semapimod.png

 

Patent Submitted Granted
NORMALIZATION OF CULTURE OF CORNEAL ENDOTHELIAL CELLS [US2015044178] 2012-12-27 2015-02-12
Patent Submitted Granted
Neural tourniquet [US2005282906] 2005-12-22
Guanylhydrazone Salts, Compositions, Processes of Making, and Methods of Using [US2008262090] 2008-10-23
Protective role of semapimod in necrotizing enterocolitis [US7795314] 2007-12-06 2010-09-14
METHOD OF TREATING ILEUS BY PHARMACOLOGICAL ACTIVATION OF CHOLINERGIC RECEPTORS [US2011112128] 2011-05-12
Method of treating ileus by pharmacological activation of cholinergic receptors [US2007213350] 2007-09-13
Pharmaceutically active aromatic guanylhydrazones [US2005171176] 2005-08-04
Guanylhydrazone salts, compositions, processes of making and methods of using [US7244765] 2006-01-19 2007-07-17
GUANYLHYDRAZONE SALTS, COMPOSITIONS, PROCESSES OF MAKING, AND METHODS OF USING [US8034840] 2008-06-19 2011-10-11
METHOD FOR TREATING GLIOBLASTOMAS AND OTHER TUMORS [US2014323576] 2014-03-14 2014-10-30
Methods of treatment of fatty liver disease by pharmacological activation of cholinergic pathways [US8865641] 2012-06-14 2014-10-21
Semapimod
Semapimod cs.svg
Semapimod sf.gif
Systematic (IUPAC) name
N,N’-bis[3,5-bis[N-(diaminomethylideneamino)-C-methylcarbonimidoyl]phenyl] decanediamide tetrahydrochloride
Identifiers
CAS Number 164301-51-3 Yes
352513-83-8 (base)
ATC code None
PubChem CID: 5745214
UNII 9SGW2H1K8P Yes
ChEMBL CHEMBL2107779
Chemical data
Formula C34H56Cl4N18O2
Molecular mass 890.73984 g/mol

see………http://worlddrugtracker.blogspot.in/2015/12/semapimod.html

/////////Semapimod Mesylate,  CPSI-2364,  AXD-455,  CN-149, PHASE 1, FERRING, CNI 1493

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


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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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