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Showing posts with label Antagonist. Show all posts
Showing posts with label Antagonist. Show all posts

Monday, 7 December 2015

Tesmilifene , Antagonist of intracellular histamine

BMS-217380; BMY-33419; DPPE
CAS No. 98774-23-3(Tesmilifene),  92981-78-7(Tesmilifene hydrochloride)
CAS  98774-23-3
MW 283.41
Percent Composition: C 80.52%, H 8.89%, N 4.94%, O 5.65%

CAS 92981-78-7
 BMS-217380-01; BMY-33419
MF 319.87
Percent Composition: C 71.34%, H 8.19%, N 4.38%, O 5.00%, Cl 11.08%
Properties: White crystals from isopropanol + acetone (3:1), mp 156-158°. pKa 10.9.
Melting point: mp 156-158°
pKa: pKa 10.9
Therap-Cat: Antineoplastic adjunct (chemosensitizer).
Tesmilifene is a novel potentiator of chemotherapy which, when added to doxorubicin, achieved an unexpected and very large survival advantage over doxorubicin alone in a randomized trial in advanced breast cancer.
PHASE 23 FOR An estrogen receptor antagonist potentially for the treatment of advanced breast cancer, gastric cancer
Tesmilifene is a novel agent that augments cytotoxicity of various chemotherapeutic agents both in vitro and in vivo. It binds selectively to the high-affinity microsomal antiestrogen binding site (Ki=50nm) but has no affinity for estrogen receptors. Inhibits concanavalin-A-induced histamine release in mast cells and acts as a novel antagonist of intracellular histamine.
US 4803227


The target product can be prepared by reacting para-benzylphenol (I) with 2-diethylaminoethylchloride hydrochloride (II) either by means of NaOH in H2O or with K2CO3 in DMF/acetone (at 60 C in both cases), followed by treatment with HCl to obtain the corresponding hydrochloride salt.
 EP 0153160; JP 1985190742; US 4803227
 US 4803227
Tesmilifene is a small molecule chemopotentiator under development by YM BioSciences, a Candian pharmaceutical company that specialises in the development of cancer treatments. It is indicated for use in combination with standard cytotoxic drugs, such as taxanes and anthracyclines, which are widely used in the treatment of metastatic disease – when cancers spread to distant sites in the body.
Tesmilifene, the company's lead investigational compound, is currently in phase III development for patients with metastatic breast cancer. At the end of January 2007, an independent safety monitoring board advised the company that its ongoing registration trial should be stopped; it was considered unlikely that significant differences in overall survival (primary endpoint) between treatment arms would emerge over time. The company had hoped that the addition of tesmilifene to standard epirubicin/cyclophosphamide therapy would confer a survival benefit similar to that seen in its earlier phase III trial.
In light of these disappointing results, YM BioSciences plans a detailed analysis of its phase III data in advanced breast cancer to see if it can identify why tesmilifene failed to add clinical benefit in this trial.
Cytotoxic drugs have proved potent weapons in the fight against malignant tumours and are considered first-line therapy for the treatment of many cancers. However, while patients often respond well to a first course of chemotherapy over time the response to drug treatment diminishes and the tumour may eventually become drug resistant. In some cases resistance can develop across several classes of anti-cancer drugs, leading to multidrug resistance. The development of drug resistance limits the effectiveness of many anti-cancer agents and is an important contributor to cancer deaths.
The development of agents that can overcome drug resistance is seen as one of the most important areas of cancer research and for which there is significant unmet need. Various approaches are being explored to boost the use of cytotoxic agents including chemopotentiators, chemoprotectants and liposomal formulations.
Clearly any agent that can prevent or reverse drug resistance would have a major impact on treatment strategies, enhancing the benefits of standard cytotoxic drugs.
Anthracyclines are a class of cytotoxic agents with proven efficacy in the treatment of breast cancer. They include agents such as doxorubicin and epirubicin among others. Because patients with metastatic breast cancer may have received anthracycline therapy for earlier stage breast cancer (adjuvant therapy) or following disease recurrence, there is a risk that they will fail to respond to continued treatment.
A phase III trial in 305 patients with advanced breast cancer has shown that when tesmilifene is combined with doxorubicin it appears to improve survival over treatment with doxorubicin alone. In this trial approximately half the patients were treated with both tesmilifene and doxorubicin, while the other half received doxorubicin alone. Although there were no significant differences in tumour response rates, progression-free survival, or average duration of response between treatment arms at endpoint, overall survival was significantly improved in the combination arm. Among patients treated with tesmilifene and doxorubicin overall survival was 23.6 months compared with 15.6 months for those treated with doxorubicin alone.
Researchers have suggested that tesmilifene may enhance the anti-tumour effects of anthracyclines in several ways:
  • Reducing the cancer cell's ability to become resistant
  • Decreasing the metabolism or "break-down" of doxorubicin
  • Disrupting the cancer cell's energy source
In March 2004 YM BioSciences began its pivotal international phase III trial of tesmilifene in metastatic breast cancer. By September 2005, 723 patients had been enrolled in the trial, which was designed once again to compare the efficacy and safety of tesmilifene and an antrhacycline (epirubicin) with epirubicin alone.
"At the end of January 2007, an independent safety monitoring board advised the company that its ongoing registration trial should be stopped."
Given the survival benefit seen in the earlier trial, which was carried out by the Canadian National Cancer Institute, the company was optimistic about outcome in its pivotal registration trial. However, an interim analysis of 351 events suggested that significant differences in overall survival were unlikely to be seen between the two treatment arms as the data matured and the trial was brought to a premature end.
In addition to its work on anthracyclines, YM BioSciences has also been exploring the potential of tesmilifene to enhance the efficacy of taxanes, also standard chemotherapy for metastatic breast cancer. Other potential applications include:
  • Adjuvant therapy for breast cancer, i.e. immediately post-surgery and before the cancer has recurred or metastasised
  • Hormone-refractory prostate cancer
  • Lung cancer
  • Non-Hodgkin's lymphoma
Although there have been major advances in the treatment of breast cancer in the last 10 to 15 years, it remains a disease for which improved treatments are still urgently needed. Estimates from the WHO suggest that metastatic breast cancer will claim the lives of over 40,000 patients a year.
Current treatments for metastatic breast cancer are rarely curative but can nonetheless do much to improve patients' quality of life or duration of survival. . By boosting the cytotoxic effects of standard chemotherapy agents such as anthracyclines, while protecting healthy cells, tesmilifene was thought to have potential to extend the benefits of cytotoxic therapy to more patients. This is now in doubt following premature ending of its pivotal registration trial in advanced breast cancer.
Literature References: Intracellular histamine antagonist with chemopotentiating and cytoprotective activity. Structurally similar to tamoxifen, q.v., although binds anti-estrogen binding site (AEBS) with no affinity for the estrogen receptor.
Prepn: L. J. Brandes, M. W. Hermonat, Biochem. Biophys. Res. Commun. 123, 724 (1984); and use as antineoplastic: eidem, US 4803227 (1989 to Univ. Manitoba); and study of binding affinity: M. Poirot et al., Bioorg. Med. Chem. 8, 2007 (2000). Spectral analysis of interaction with P450 isozymes: L. J. Brandes et al., Cancer Chemother. Pharmacol. 45, 298 (2000).
Clinical evaluation in combination with cyclophosphamide in prostate cancer: L. J. Brandes et al., J. Clin. Oncol. 13, 1398 (1995); in combination with doxorubicin in breast cancer: L. Reyno et al., J. Clin. Oncol. 22, 269 (2004).
Bioorg Med Chem 2000,8(8),2007
Neoadjuvant treatment of Breast Cancer [US2008318880]2008-12-25 
Selective androgen receptor modulators for treating diabetes [US2007281906]2007-12-06 
Nuclear receptor binding agents [US8158828]2007-11-152012-04-17
Treatment of hormone-refractory prostate cancer [US2004220281]2004-11-04 
Treatment of metastatic breast cancer with anthracyclines, and taxanes [US2006089317]2006-04-27 
Serm reduction of lipid profiles [US2007135407]2007-06-14 
Use of a combination of dppe with other chemotherapeutic agents for the treatment of breast cancer [US2006142287]2006-06-29 
Neoadjuvant treatment of breast cancer [US2006160755]2006-07-20 

Product Literature References

Enhancement of cytotoxicity of natural product drugs against multidrug resistant variant cell lines of human head and neck squamous cell carcinoma and breast carcinoma by tesmilifene.: P. J. Ferguson, et al.; Cancer Lett. 274, 279 (2009), Abstract;
Phase III study of N,N-diethyl-2-[4-(phenylmethyl) phenoxy]ethanamine (BMS-217380-01) combined with doxorubicin versus doxorubicin alone in metastatic/recurrent breast cancer: National Cancer Institute of Canada Clinical Trials Group St: L. Reyno, et al.; J. Clin. Oncol. 22, 269 (2004), Abstract;
Synergy between tamoxifen and cisplatin in human melanoma cells is dependent on the presence of antiestrogen-binding sites.: J.A. Jones, et al.; Cancer Res. 57, 2657 (1997), Abstract;
Influence of DPPE on histamine release from isolated rat mast cells.: N. Grosman; Agents Actions 41, 1 (1994), Abstract;
Histamine is an intracellular messenger mediating platelet aggregation.: S.P: Saxena, et al.; Science 243, 1596 (1989), Abstract;

///////Tesmilifene, Antineoplastic Adjunct, Chemosensitizer, PHASE 3, Tesmilifene hydrochloride, BMY-33419, BMS-217380, DPPE, N,N-DPPE, Antagonist of intracellular histamine