DSR-141562 is a new compound that can be taken orally and has a specific ability to inhibit phosphodiesterase 1 (PDE1) in the brain. This compound exhibits a preference for inhibiting human PDE1B, with an IC50 value of 43.9 nM. It also shows moderate inhibition of human PDE1A (IC50 = 97.6 nM) and PDE1C (IC50 = 431.8 nM). DSR-141562 is particularly useful in the study of positive symptoms, negative symptoms, and cognitive impairments associated with schizophrenia.

PDE1B (human):43.9 nM (IC50), PDE1A (human):97.6 nM (IC50), PDE1C (human):431.8 nM (IC50)

DSR-141562, when administered orally to rats and monkeys, demonstrates effective brain uptake and pharmacological activity across multiple dosages and time points. At a single dose of 30 mg/kg, it achieves good brain penetration, evidenced by a brain-to-blood concentration ratio of 0.99 in rats, and exhibits significant pharmacological effects at various intervals post-administration (0.5, 1, 2, and 3 hours). A lower dose of 10 mg/kg, given 2 hours prior, modestly yet significantly enhances cGMP levels in the frontal cortex and striatum of rats. This compound, at doses of 30 mg/kg or 100 mg/kg, notably increases cGMP concentration in monkey cerebrospinal fluid (CSF) after 2 hours, with plasma concentrations of the unbound drug exceeding 43.9 nM, which is its IC50 for PDE1B inhibition in vitro. Furthermore, DSR-141562 effectively counteracts methamphetamine-induced hyperactivity in rats at 3 mg/kg, 10 mg/kg, and 30 mg/kg doses without affecting spontaneous locomotor activity at the lower doses of 3 and 10 mg/kg. Likewise, it significantly mitigates the phencyclidine-induced decline in social interaction in mice at doses of 0.3 mg/kg, 1 mg/kg, and 3 mg/kg. These findings demonstrate DSR-141562's potential in modulating neural activity and behavior in animal models through its pharmacological actions on cGMP levels and its ability to penetrate the brain, suggesting its therapeutic relevance.