ANTAGONIST TO THE NAADP RECEPTOR - Isis Project No 2944

Ned-19 lends itself as a potential treatment for any disease that is modulated by NAADP driven calcium release. This includes multiple sclerosis, asthma and hypertension, diabetes and cardiac disorders.

Marketing Opportunity

Calcium signalling is responsible either directly, or indirectly for a wide variety of cellular functions.  It is initiated via a messenger molecule that is produced within the cell in response to external stimuli. Nictinic acid adenine dinucleotide phosphate (NAADP) is such a messenger molecule and has the most potent ability to release calcium from intracellular stores. NAADP is thought to play an important role in health and disease.

The Oxford Invention

Researchers at Oxford University have discovered a unique compound, which is an effective inhibitor of NAADP-mediated calcium release. The discovery was made using a database of commercially available compounds and software provided by OpenEye, to search for molecules with the same look (3D structure) and feel (electrostatic properties) as NAADP. This differs from more traditional methods that start with a natural chemical and systemically modify its structure to discover new drugs. The novel approach used here led to the identification of Ned-19. Ned-19 is small (516Da), highly specific, and cell permeable. These properties make Ned-19 a drug-like molecule according to Lipinski’s ‘Rule of 5’ criteria. The compound can easily access its intracellular target because it is cell permeant due to its small size and hydrophobicity. It is highly selective not only in regard to other calcium release pathways, such as IP-3 and cADPR (≥ 10,000-fold) but it also does not interfere with any of the other ion channels in the plasma membrane. It is effective at nanomolar concentrations so only a small quantity is needed to exert its effect (IC50 (half inhibitory concentration) of 3 nM). Structural activity studies suggest that differences in chemical selectivity exist not only between organisms but also between tissues. This supports the idea of developing tissue-selective drugs. The current research work focuses on the use of Ned-19 to relax airway smooth muscle cells as a possible treatment for asthma.

Chemical structures (A) & Ca2+ release dose-inhibition curves (B). Colours represent similar functional group mimics.

Patent Status

This work is the subject of patent application, and Isis would like to talk to companies interested in developing the commercial opportunity that this represents. Please contact the Isis Project Manager to discuss this further.

Request Further Information: Project Number 2944 - Antagonist to the NAADP Receptor