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cilomilast, and roflumilast caused significant side effects, including
nausea and vomiting, at therapeutic doses in human clinical trials.
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 signaling, 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. 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.
- deCODE Breast Cancer. In October, deCODE launched deCODE
BreastCancer(TM), the company's latest DNA-based disease risk test, for
assessing individual risk of the common forms of breast cancer and
personalizing screening and treatment strategies. The seven markers
measured by the test, discovered by deCODE and others, contribute to
the incidence of an estimated 60 percent of all breast cancers. The
test integrates data from discovery and replication studies published
in major peer-reviewed journals and involving nearly 100,000 breast
cancer patients and healthy volunteers from many populations. The test
can identify the roughly 5 percent of women who are at a greater than
20 percent lifetime risk of the common
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