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Treatment of Schistosomiasis Using Substituted Oxadiazole 2-Oxides

Posted Mar 22 2009 5:00pm

Description of Invention:
Available for licensing and commercial development are pharmaceutical compositions and methods for the treatment of Schistosomiasis in mammals. The various compositions are based on a number of compounds derived from 1,2,5-oxadiazole that are potent inhibitors of thioredoxin glutathione reductase (TGR), a critical parasite redox protein.

Schistosomiasis is a chronic disease caused by trematode flatworms of the genus Schistosoma, including S. mansoni, S. japonicum and S. haematobium. Adult schistosome parasites live in an aerobic environment within human hosts, and therefore must have effective mechanisms to maintain cellular redox balance. Additionally, the worms must be able to evade reactive oxygen species generated by the host's immune response. In most eukaryotes there are two major systems to detoxify reactive oxygen species, one based on the tripeptide glutathione and the other based on the protein thioredoxin. Glutathione reductase (GR) reduces glutathione disulfide, whereas thioredoxin reductases (TrxR) are pivotal in the Trx-dependent system. It was recently discovered that specialized TrxR and GR enzymes are absent in schistosomes. Instead, they are replaced by the unique multifunctional enzyme TGR. This reliance on a single enzyme for both glutathione disulfide and thioredoxin reduction suggests that the parasite's redox systems are subject to a bottleneck dependence on TGR, and that TGR represents a potentially important drug target.

Schistosomiasis remains a major and neglected health problem in many tropical areas. The health burden resulting from Schistosomiasis is estimated to include more than 200 million people infected, 779 million at risk of infection, 280,000 deaths annually, and more than 20 million individuals experiencing high morbidity. Clinical manifestations of schistosomiasis infection include abdominal pain, cough, diarrhea, eosinophilia, fever, fatigue, and hepatosplenomegaly. The primary route of infection occurs through contact with infected river and lake water, at which time the parasite burrows into the skin, matures, then migrates to other areas of the body. Adult schistosome parasites reside in the mesenteric veins of their human hosts, where they can survive for up to 30 years. The need to control schistosomiasis is acute and efforts have been ongoing for years on three main fronts: prevention (via establishment and maintenance of sources of safe potable water), development of a vaccine, and use of drugs to treat the infection.

Treatment of schistosomiasis.

The specific inhibition of TGR by the composition of this invention could satisfy the current need for new broad spectrum drugs to treat schistosomiasis, given the limitations of other drugs currently used or under development. Praziquantel, the only drug currently used against the infection, although stable, effective and relatively inexpensive, it must be administered on an annual or semi-annual basis. Furthermore, there are preliminary reports of praziquantel-resistant cases. Arteminisinin has shown promise as a new drug for the treatment of schistosomiasis, but its use must be restricted in areas of malaria transmission so that its use as an antimalarial is not put at risk. Oxamniquine, a tetrahydroquinoline derivative, is effective only against S. mansoni and resistance has been reported, further reducing its potential value in schistosomiasis control.

Development Status:
To date, the general oxidiazole-2-oxide chemotype described here has shown efficacy in animal models. Efforts to define the pharmacophore and optimize this chemotype in terms of potency, efficacy and selectivity will be reported in due course. Currently, selected oxidiazole-2-oxides are being evaluated in advanced ADME/T assays and are being formulated for oral dosing experiments.

Craig J Thomas (NHGRI)

Patent Status:
HHS, Reference No. E-162-2008/0
PCT, Application No. PCT/US2009/53715 filed 13 Aug 2009

Relevant Publication:
  1. G Rai et al. Structure-mechanism insights and the role of nitric oxide donation guide the development of oxidiazole-2-oxides as targeted agents against Schistosomiasis. In preparation.
  2. G Rai, CJ Thomas, W Leister, DJ Maloney. Synthesis of oxadiazole-2-oxide analogues as potential antischistosomal agents. Tetrahedron Lett., accepted.
  3. AA Sayed, A Simeonov, CJ Thomas, J Inglese, CP Austin, DL Williams. Identification of oxadiazoles as new drug leads for the control of schistosomiasis. Nat Med. 2008 Apr;14(4):407-412. [ PubMed abs ]
  4. A Simeonov, A Jadhav, AA Sayed, Y Wang, ME Nelson, CJ Thomas, J Inglese, DL Williams, CP Austin. Schistosoma mansoni thioredoxin-glutathione reductase (TGR) inhibitors identified via quantitative high-throughput screen. PLoS Negl Trop Dis. 2007;2:1-10.

Licensing Status:
Available for licensing.

Collaborative Research Opportunity:
The NIH Chemical Genomics Center is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize appropriate lead compounds described in U.S. Provisional Application No. 61/088,970. Please contact Dr. Craig J. Thomas via e-mail ( ) for more information.

Infectious Diseases
Infectious Diseases - Therapeutics
Rare Diseases
Neglected Diseases

For Additional Information Please Contact:
Cristina Thalhammer-Reyero Ph.D., M.B.A.
NIH Office of Technology Transfer
6011 Executive Blvd. Suite 325 Room 33,
Rockville, MD 20852
United States
Phone: 301-435-4507
Fax: 301-402-0220

Ref No: 1902

Updated: 03/2009

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