BI-409306 is a potent and selective PDE9A inhibitor, with an IC50 of 52 nM, and shows weak activity against other PDEs, such as PDE1A (IC50, 1.4 µM), PDE1C (IC50, 1.0 µM), PDE2A, PDE3A, PDE4B, PDE5A, PDE6AB, PDE7A, and PDE10A (IC50 all > 10 μM). BI-409306 can be used in the research of memory enhancement in CNS disorders. It is currently being investigated in clinical trials.
Degradation of cGMP (cyclicguanosine monophosphate, a second messenger) is mediated by phosphodiesterase enzymes (PDE), of which PDE9A selectively hydrolyses cGMP with highest affinity of all PDEs. Bi-409306 is an effective and selective PDE9A inhibitor with IC50 values of 65 and 168 nM for human and rat PDE9A, respectively. At 20 minutes postintraperitoneal injection of BI-409306 1.5–15 mg/kg, a significant dose-dependent increase in extracellular cGMP levels was observed in the rat prefrontal cortex, which peaked after 20 minutes and gradually returned to control values approximately 100 minutes after the injection. Furthermore, cGMP levels in rat CSF (cerebrospinal fluid) increased in a dose-dependent manner following BI-409306 administration. Reduction of cGMP level in mouse striatum caused by NMDA (N-methyl-D-aspartate) receptor antagonist MK-801 was significantly attenuated by coadministration of BI-409306 0.5 mg/kg, with a mean increase in cGMP levels of 41% compared with MK-801 alone. When applied 60 minutes before a strong stimulus, BI-409306 significantly enhanced LTP (long-term potentiation) compared with vehicle control at 0.3 μM. Moreover, oral treatment of mice with BI-409306 at all doses tested (0.007–2.5 mg/kg) led to an attenuation or reversal of the MK-801-induced reduction in spontaneous alternation compared with the MK-801-treated group[1].
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