Anti-Coagulant, Anti-Inflammatory Nitric Oxide-Releasing Compounds and Their Conjugation

Description of Invention:
Diazeniumdiolates are compounds that contain an N₂O₂ functional group. These compounds have utility as prodrugs because they generate nitric oxide upon degradation. Nitric oxide (NO) plays a role in regulation of blood pressure, inflammation, neurotransmission, macrophage induced cytostasis, and cytotoxicity. NO is also important in the protection of the gastric mucosa, relaxation of smooth muscle, and control of the aggregation state of blood cells. A series of amidine and enamine-derived diazeniumdiolates have been produced that offer many advantages over previously known derivatives. These compounds appear to be applicable toward the wide variety of processes involving nitric oxide. A recent study demonstrated clinical potential for diazeniumdiolates in preventing vascular thickening after open vascular interventions, such as those used to treat atherosclerosis.

Applications:

• Anti-coagulant coating of medical devices, stents, and implants
• Production of NO-releasing agents from known pharmaceuticals
• Incorporate 3 pharmaceuticals in one agent (carbonyl, amine, and NO-releasing diazeniumdiolate)

Advantages:

• Not expected to decompose into carcinogenic nitrosamines
• Full range of water solubility
• Many are more heat stable and release NO slowly

Development Status:

• Early-stage
• Pre-clinical
• In vitro data available
• In vivo data available (animal)

Inventors:
Joseph A Hrabie (NCI)
Larry K Keefer (NCI)


Patent Status:
HHS, Reference No. E-067-1997/0
US, , Patent No. 6,232,336, Issued 15 May 2001
US, , Patent No. 6,511,991, Issued 28 Jan 2003
US, , Patent No. 6,750,254, Issued 15 Jun 2004
US, , Patent No. 6,911,478, Issued 28 Jun 2005


Related Technologies:
US, Patent No. 7,968,664, Issued 28 Jun 2011, Reference No. E-188-2004/0
US, Patent No. 8,093,343, Issued 10 Jan 2012, Reference No. E-188-2004/0
PCT, Application No. PCT/US2010/056446 filed 12 Nov 2010, Reference No. E-025-2010/0
US, Application No. 60/613,257 filed 27 Sep 2004, Reference No. E-188-2004/0
US, Application No. 61/261,175 filed 13 Nov 2009, Reference No. E-025-2010/0


Relevant Publication:

1. Biswas D, et al. [ PMID 20589293 ]
2. Kapadia MR, et al. [ PMID 18178471 ]
3. Dinh BT, et al. [ PMID 18068133 ]
4. Reynolds MM, et al. [ PMID 16529441 ]
5. Hrabie JA, et al. [ PMID 16149795 ]
6. Arnold EV, et al. [ PMID 12223179 ]
7. Arnold EV, et al. [ PMID 11950353 ]
8. Hrabie JA, et al. [ PMID 11942789 ]
9. Hrabie JA, et al. [ PMID 10970319 ]

For Licensing Information Please Contact:
Betty Tong Ph.D.
NIH Office of Technology Transfer
6011 Executive Blvd. Suite 325,
Rockville, MD 20852
United States
Email: tongb@mail.nih.gov
Phone: 301-594-6565
Fax: 301-402-0220


Ref No: 2346

Updated: 01/2012