[Federal Register Volume 74, Number 59 (Monday, March 30, 2009)]
[Notices]
[Pages 14139-14141]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E9-6935]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


Government-Owned Inventions; Availability for Licensing

AGENCY: National Institutes of Health, Public Health Service, HHS.

ACTION: Notice.

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SUMMARY: The inventions listed below are owned by an agency of the U.S. 
Government and are available for licensing in the U.S. in accordance 
with 35 U.S.C. 207 to achieve expeditious commercialization of results 
of Federally-funded research and development. Foreign patent 
applications are filed on selected inventions to extend market coverage 
for companies and may also be available for licensing.

ADDRESSES: Licensing information and copies of the U.S. patent 
applications listed below may be obtained by writing to the indicated 
licensing contact at the Office of Technology Transfer, National 
Institutes of Health, 6011 Executive Boulevard, Suite 325, Rockville, 
Maryland 20852-3804; telephone: 301/496-7057; fax: 301/402-0220. A 
signed Confidential Disclosure Agreement will be required to receive 
copies of the patent applications.

Treatment of Schistosomiasis Using Substituted Oxadiazole 2-Oxides

    Description of Technology: 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,

[[Page 14140]]

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.
    Applications: Treatment of schistosomiasis.
    Advantages: 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, 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 oxadiazole-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 oxadiazole-2-oxides are being evaluated in advanced 
ADME/T assays and are being formulated for oral dosing experiments.
    Inventors: Craig J. Thomas (NHGRI) et al.

Publications

    1. G Rai et al. Structure-mechanism insights and the role of nitric 
oxide donation guide the development of oxadiazole-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.
    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.

    Patent Status: U.S. Provisional Application No. 61/088,970 filed 14 
Aug 2008, entitled ``Oxadiazole-2-Oxides as Antischistosomal Agents'' 
(HHS Reference No. E-162-2008/0-US-01).
    Licensing Status: Available for licensing.
    Licensing Contact: Cristina Thalhammer-Reyero, Ph.D., MBA; 301-435-
4507; [email protected].
    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 ([email protected]) for more information.

Dendrimer Conjugates Targeting Adenosine Receptors, P2Y Receptors and 
Other Receptors of the GPCR Superfamily, for Use in the Treatment of 
Various Disorders, Including Neurodegenerative Diseases, Stroke, 
Epilepsy, Pain and Thrombosis

    Description of Technology: Available for licensing and commercial 
development are conjugate compositions useful in the treatment of a 
variety of diseases, comprising a dendrimer and a ligand. The ligand is 
a functionalized congener of an agonist or antagonist of a receptor of 
the G-protein coupled receptor (GPCR) superfamily. More specifically, 
the invention focuses on several agonists and antagonists of 
A1, A2A, A2B, and A3 
adenosine receptors and P2Y receptors, all members of the GPCR 
superfamily. For example, an agonist of the A1 adenosine 
receptor is useful for treating a number of diseases including 
neurodegeneration, stroke, epilepsy, and pain. Antithrombotic treatment 
is another example of the use of this dendrimer technology. Dendrimers 
are polymers made from branched monomers through the iterative organic 
synthesis by adding one layer at each step to provide a symmetrical 
structure. Certain drugs, such as taxol, cisplatin, methotrexate, and 
ibuprofen, have been covalently linked to dendrimers in a reversible 
fashion. However, dendrimer conjugates in this application are 
biologically active without cleavage of the drug or cellular uptake. 
The conjugate of the invention can include any suitable dendrimer, 
particularly a poly(amidoamine) (PAMAM) dendrimer. The invention 
further provides pharmaceutical compositions and methods of treating 
various diseases and diagnostic methods employing such conjugates.

Applications

     Treatment of a number of diseases involving receptors of 
the GPCR superfamily.
     Determination of a potential treatment of a patient with 
an agonist or antagonist or receptors of the GPCR superfamily.
    Advantages: The dendrimer conjugates described in this invention 
have one or more advantages over corresponding monomeric drugs, 
including altered pharmacokinetics, decreased toxicity, increased 
solubility, enhanced potency or selectivity due to the multivalency.
    Development Status: The development is still in the early stages.
    Inventors: Kenneth A. Jacobson et al. (NIDDK).
    Relevant Publications: The published patent applications are listed 
below. In addition, the technology is further described in the 
following publications:

    1. Y Kim, B Hechler, A Klutz, C Gachet, KA Jacobson. Toward 
multivalent signaling across G protein-coupled receptors from 
poly(amidoamine) dendrimers. Bioconjug Chem. 2008 Feb;19(2):406-411.
    2. Y Kim, AM Klutz, KA Jacobson. Systematic investigation of 
polyamidoamine dendrimers surface-modified with poly(ethylene glycol) 
for drug delivery applications: Synthesis, characterization, and 
evaluation of cytotoxicity. Bioconjug Chem. 2008 Aug;19(8):1660-1672.
    3. Y Kim, AM Klutz, B Hechler, ZG Gao, C Gachet, KA Jacobson. 
Application of the functionalized congener approach to dendrimer-based 
signaling agents acting through A2A adenosine receptors. 
Purinergic Signal. 2009 Mar;5(1):39-50.
    4. AA Ivanov and KA Jacobson. Molecular modeling of a PAMAM-
CGS21680 dendrimer bound to an A2A adenosine receptor 
homodimer. Bioorg Med Chem Lett. 2008 Aug 1;18(15):4312-4315.

[[Page 14141]]

    5. AM Klutz, ZG Gao, J Lloyd, A Shainberg, KA Jacobson. Enhanced 
A3 adenosine receptor selectivity of multivalent nucleoside-
dendrimer conjugates. J Nanobiotechnol. 2008 Oct 23;6:12.

Patent Status

     U.S. Provisional Application No. 60/947,121 filed 20 Jun 
2007 (HHS Reference No. E-219-2007/0-US-01).
     U.S. Provisional Application No. 61/045,498 filed 16 Apr 
2008 (HHS Reference No. E-219-2007/1-US-01).
     International Application No. PCT/US08/067683 filed 20 Jun 
2008, which published as WO2009/006046 on 08 Jan 2009 (HHS Reference 
No. E-219-2007/2-PCT-01).
     U.S. Patent Application No.12/143,451 filed 20 Jun 2008, 
which published as U.S. 20090012035 on 08 Jan 2009 (HHS Reference No. 
E-219-2007/2-US-02).
    Licensing Status: Available for licensing.
    Licensing Contact: Cristina Thalhammer-Reyero, PhD, MBA; 301-435-
4507; [email protected].
    Collaborative Research Opportunity: The Laboratory of Bioorganic 
Chemistry of the National Institute of Diabetes & Digestive & Kidney 
Diseases is seeking statements of capability or interest from parties 
interested in collaborative research to further develop, evaluate, or 
commercialize dendrimer conjugates of suitably functionalized small 
molecule ligands of adenosine receptors and P2Y nucleotide receptors. 
Please contact Dr. Kenneth A. Jacobson at 301-496-9024, or e-mail 
[email protected], for more information.

    Dated: March 19, 2009.
Richard U. Rodriguez,
Director, Division of Technology Development and Transfer, Office of 
Technology Transfer, National Institutes of Health.
[FR Doc. E9-6935 Filed 3-27-09; 8:45 am]
BILLING CODE 4140-01-P