We recently described a novel series of aminopyridopyrazinones as PDE5 inhibitors. Efforts toward optimization of this series culminated in the identification of 3-[4-(2-hydroxyethyl)piperazin-1-yl]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one, which possessed an excellent potency and selectivity profile and demonstrated robust in vivo blood pressure lowering in a spontaneously hypertensive rat (SHR) model. Furthermore, this compound is brain penetrant and will be a useful agent for evaluating the therapeutic potential of central inhibition of PDE5. This compound has recently entered clinical trials.
We report on the influence of molecular chemical structure on second harmonic activity in several homologous series of self-assembling short chain polymers containing both molecularly rigid and flexible segments and known to form supramolecular nanostructures. The second-order nonlinear optical susceptibility and physical structure of films formed by these molecules were investigated by second harmonic generation experiments and small-angle X-ray scattering. It was observed that all series of molecules formed polar films with a layered structure by self-assembly. The nonlinear susceptibilities were found to increase with the ratio of first hyperpolarizability to layer period in the self-assembled films, further suggesting spontaneous polar order in these layers of supramolecular structures.
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