deCODE genetics announced the filing of an investigational new drug (IND) application for DG071, the company's novel small-molecule modulator of phosphodiesterase 4 (PDE4), with the US Food and Drug Administration (FDA). The compound is being developed as a new and potentially safer means of targeting PDE4 to combat memory loss and cognitive deficits associated with Alzheimer's disease and other disorders in which neural signalling is reduced or impaired.

In animal models, DG071 has been shown to significantly improve learning and long- and short-term memory at doses that offer a wide margin for safety and tolerability. The compound has the potential to eliminate the nausea that limits the utility of previous PDE4 inhibitors. deCODE plans to advance the clinical development of DG071 with a strategic partner.

"This compound has exciting therapeutic potential and reflects the exceptional capabilities of our drug discovery and structural biology groups. Our teams used protein crytallography to determine the structure of domains that regulate the enzymatic activity of PDE4, and in DG071 discovered a compound that binds to the PDE4 regulatory domain and effectively modulates the activity of the enzyme. DG071 has been shown in several animal models to potently and specifically improve cognitive function, and features a much wider safety and tolerability profile than existing PDE4 inhibitors. This is encouraging, as many of the amyloid-busting therapeutics currently entering clinical trials in Alzheimer's disease have the potential to slow or stop progression of the disease but will not reverse the destruction of neurons. Our expectation is that DG071 will allow the remaining neurons to store and retrieve memories more efficiently. DG071 could be useful in the treatment not only of Alzheimer's disease, but might also have benefit in untington's disease, schizophrenia, anxiety, ADHD and depression," said Dr Kari Stefansson, CEO of deCODE.

DG071 is a novel, potent and selective PDE4D modulator discovered by deCODE's chemistry group. First and second generation PDE4 inhibitors such as rolipram, cilomilast, and roflumilast caused significant side effects, including nausea and vomiting, at the therapeutic doses in human clinical trials. Such side effects severely limit the utility of these earlier compounds. Data generated at deCODE suggest that the observed side effects were closely correlated with the binding of these molecules in the PDE4 enzymatic active site competitively with cAMP. As cAMP is of critical importance to neuronal signalling the goal of deCODE's program has been to discover compounds that would modulate PDE4 activity via an allosteric mechanism to improve safety and tolerability.

Towards this goal, the deCODE biostructures team solved multiple novel co-crystal structures of PDE4D & PDE4B containing regulatory domains with bound ligands. Those structures allowed the deCODE chemistry team to identify a novel binding site for allosteric modulators in the PDE4 regulatory domain. Binding of an allosteric modulator at that site is non-competitive with cAMP. DG071 has been shown in animal models to improve cognitive function with benefit similar to that of cholinesterase inhibitors such as donepezil that currently are a mainstay of therapy for memory loss in early Alzheimer's disease, yet also benefiting long term memory function in animal tests where the cholinesterase inhibitors are ineffective.

deCODE has developed a broad proprietary platform for PDE4 modulators that the company is applying to discover compounds with potential utility for the treatment of over-active bladder, inflammatory and respiratory diseases.

deCODE is a biopharmaceutical company applying its discoveries in human genetics to the development of diagnostics and drugs for common diseases.

deCODE chemistry, Inc & deCODE biostructures, Inc, are wholly-owned subsidiaries of deCODE genetics providing contract research services to pharmaceutical companies, biotechnology companies, academic institutions, and government facilities.