Biological Activity
pf-2545920 is an inhibitor of phosphodiesterase 10a (pde10a) with ic50 value of 0.37nm [1].pde10a is highly expressed in the medium spiny neurons of the striatum and regulates both cgmp and camp. the pde10a inhibitors are believed to regulate cyclic nucleotide signaling in the cortices-triatothalamic circuit. previous inhibitors of pde have potential therapeutic utility but also have potential safety risks due to off-target pde inhibition. thereby pf-2545920 is developed as a more selective inhibitor. pf-2545920 is shown to be efficacious both in vitro and in vivo with improved penetration in cns. it has excellent in vivo efficacy in neurochemical elevation of cyclic nucleotides and in models predictive of antipsychotic activity. administration of pf-2545920 to mice can cause increase in striatal cgmp with the minimal effective dose at about 1mg/kg [1].
References
[1] verhoest pr, chapin ds, corman m, fonseca k, harms jf, hou x, marr es, menniti fs, nelson f, o'connor r, pandit j, proulx-lafrance c, schmidt aw, schmidt cj, suiciak ja, liras s. discovery of a novel class of phosphodiesterase 10a inhibitors and identification of clinical candidate 2-[4-(1-methyl-4-pyridin-4-yl-1h-pyrazol-3-yl)-phenoxymethyl]-quinoline (pf-2545920) for the treatment of schizophrenia. j med chem. 2009 aug 27;52(16):5188-96.
