DSR-141562 is a novel orally available and brain-penetrantPDE 1 inhibitor. It has preferential selectivity for predominantly brain-expressed PDE1B over other PDE1 family members, and high selectivity for the PDE1 family over otherPDE families and 65 other tested biologic targets.
Cyclic nucleotide phosphodiesterases (PDEs) are enzymes that regulate intracellular signaling by catalyzing the hydrolysis of the second messenger 3’,5’-cAMP and/or 3’,5’-cGMP. DSR-141562 is a novel orally available and brain-penetrant PDE1 inhibitor with an IC50 of 43.9 nM for human PDE1B. DSR-141562 (10 mg/kg; orally) slightly elevated the cGMP concentration, and it potently enhanced the increase of cGMP induced by a dopamine D1 receptor agonist in mouse brains. The cGMP level in monkey cerebrospinal fluid was also elevated after treatment with DSR-141562 at 30 and 100 mg/kg and could be used as a translational biomarker. DSR-141562 (3-30 mg/kg) potently inhibited methamphetamine-induced locomotor hyperactivity in rats. Furthermore, DSR-141562 (0.3-3 mg/kg) reversed social interaction and novel object recognition deficits induced by repeated treatment with an N-methyl-D-aspartate receptor antagonist, phencyclidine, in mice and rats, respectively. In common marmosets, DSR-141562 (3 or 30 mg/kg) improved the performance in object retrieval with detour tasks. These results suggest that DSR-141562 is a therapeutic candidate for positive, negative, and cognitive symptoms in schizophrenia[2].
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