MEDI 271 |
| Phosphodiesterase type 4 (PDE4) enzymes catalyse the removal of the key intracellular messenger molecule, cyclic adenosine monophosphate (cAMP), and PDE4 inhibitors are currently being developed as therapeutic agents for respiratory diseases such as asthma. Inhibition of PDE4 by the archetypal inhibitor, (R)-rolipram (1), is complicated by the existence of two distinct conformational states for the enzyme with distinct affinities for it: a High Affinity Rolipram-Binding State (HARBS) and a Low Affinity Rolipram-Binding State (LARBS). Rolipram and some other inhibitors have been found to cause a profound intracellular relocation of PDE4 sub-type A into foci. To probe a possible link between HARBS-PDE4 and foci formation, we are synthesising conformationally constrained analogues (2 and 3) of 1 that may resemble its HARBS- and LARBS-PDE4-bound conformations.
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Poster Session
7:00 PM-9:00 PM, Wednesday, August 22, 2007 BCEC -- Exhibit Hall - B2, Poster
Division of Medicinal Chemistry |
