E8-8218. Government-Owned Inventions; Availability for Licensing

AGENCY:

National Institutes of Health, Public Health Service, HHS.

ACTION:

Notice.

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: [phone]; fax: [phone]. A signed Confidential Disclosure Agreement will be required to receive copies of the patent applications.

Substituted 3,6-diphenyl-7H-[1,2,4] triazolo[3,4-b] [1,3,4] Thiadiazines as Potent Inhibitors of PDE4A, PDE4B, and PDE4D

Description of Technology: Phosphodiesterase 4 (PDE4) is a major cAMP-metabolizing enzyme found in immune and inflammatory cells, airway smooth muscle, and pulmonary nerves. It plays a significant role within the inflammatory responses associated with asthma and chronic obstructive pulmonary disease (COPD) and its modulation has been linked to memory enhancement and depression. Due to its widespread therapeutic potential, PDE4 inhibitors are highly sought after agents for treating numerous disease states. While several PDE4 inhibitors have already advanced into clinical settings, unfavorable side effects including emesis, nausea, and abdominal pain emphasize the need for novel chemotypes with potent and selective PDE4 inhibition.

This technology describes a series of substituted 3,6-diphenyl-7H-[1,2,4] triazolo[3,4-b] [1,3,4] thiadiazines that act as inhibitors of PDE4. This core structure represents a novel chemotype within extensive classes of PDE4 inhibitors and the structure activity relationships of these PDE4 inhibitors identify key binding sites and substitutions critical to the functionality for potent PDE4 inhibition. Selectivity of this novel chemotype shows weak inhibitory potency against nine PDE isoforms excluding PDE4 and strong inhibitory potency against PDE4A, PDE4B, and PDE4D. In a selectivity comparison study, the novel chemotype performs better than the PDE4 inhibitor in clinical development. Subtype-selective PDE4 inhibitors are becoming increasingly more important as new research shows that independent PDE isoforms have differential effects on cells.

Applications: Treatment of numerous diseases associated with PDE4 including asthma, COPD, inflammatory bowel disease, and other anti-inflammatory diseases with other possible treatments including depression and psychosis.

Development Status: Pre-clinical.

Publication: AP Skoumbourdis et al. Identification of a potent new chemotype for the selective inhibition of PDE4. Bioorg Med Chem Lett. 2008 Feb 15;18(4):1297-1303.

Inventors: Craig J. Thomas et al. (NHGRI).

Patent Status: U.S. Provisional Application No. 61/020,079 filed 09 Jan 2008 (HHS Reference No. E-055-2008/0-US-01).

Licensing Status: Available for licensing.

Licensing Contact: Fatima Sayyid, M.H.P.M.; 301-435-4521; [e-mail].

Nitrite and Nitrite-Methemoglobin Therapy To Detoxify Stroma-Free Hemoglobin Based Blood Substitutes

Description of Technology: Cell-free hemoglobin based oxygen carriers (HBOCs) are blood substitutes and resuscitative agents that can be used to replace whole blood donations, alleviate blood shortages and reduce the risks of infections such as HIV and hepatitis. Stroma-free HBOCs offer the advantages of increased stability, consistency of supply, and reduced immunogenicity over the use of the alternative cell based sources. However, the side effects associated with their use, including vascular toxicity, pulmonary and systemic hypertension, myocardial infarction, inflammation, and platelet aggregation severely limit their scope of clinical applications. These adverse effects are due in part to the ability of free deoxygenated hemoglobin (deoxyHb) to scavenge for nitric oxide (NO) thus rendering it unavailable for vasodilating blood vessels.

This technology is a method of using nitrites to reduce the deleterious effects associated with HBOC use as blood substitutes. Free nitrites or nitrite-methemoglobin when added to stroma-free HBOCs are converted to NO and N2O3 which escapes the scavenging activity of deoxyHb and thus is free to vasodilate blood vessels. This maintains oxygen release and NO delivery enabling improved clinical outcomes. Recent studies, using this technology as a blood substitute, have led to a reversal of vasoconstriction, hypertension and hemorrhagic shock in animal models. This new approach also reduces the toxicity associated with the use of HBOCs as a blood substitute and may allow the widespread use of HBOCs as an alternative to cell based sources. In combination with this technology, HBOC blood substitutes may now be used to efficiently deliver therapeutic agents and maintain organ perfusion during trauma and surgery.

Advantages: Reduced toxicity of cell free hemoglobin blood substitutes; Increased blood perfusion in patients; Decreased dependence on blood donations.

Development Status: Pre-clinical.

Inventors: Mark T. Gladwin (NHLBI) et al.

Publication: S Basu, R Grubina, J Huang, J Conradie, Z Huang, A Jeffers, A Jiang, X He, I Azarov, R Seibert, A Mehta, R Patel, SB King, N Hogg, A Ghosh, MT Gladwin, DB Kim-Shapiro. Catalytic generation of N2O3 by the concerted nitrite reductase and anhydrase activity of hemoglobin. Nat Chem Biol. 2007 Dec;3(12):785-794.

Patent Status: U.S. Provisional Application No. 60/996,530 filed 31 Aug 2007 (HHS Reference No. E-259-2007/0-US-01).

Licensing Status: Available for licensing.

Licensing Contact: Fatima Sayyid, M.H.P.M.; 301-435-4521; [e-mail].

Dated: April 8, 2008.

Steven M. Ferguson,

Director, Division of Technology Development and Transfer, Office of Technology Transfer, National Institutes of Health.