title: Pharmacological characterization of a novel potent, selective, and orally active phosphodiesterase 10A inhibitor, PDM-042 [(E)-4-(2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)vinyl)-6-(pyrrolidin-1-yl)pyrimidin-4-yl)morpholine] in rats: potential for the treatment of schizophrenia.
abstract: Recently, we identified a novel phosphodiesterase 10A (PDE10A) inhibitor, PDM-042 ((E)-4-(2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)vinyl)-6-(pyrrolidin-1-yl)pyrimidin-4-yl)morpholine). PDM-042 showed potent inhibitory activities for human and rat PDE10A with IC50values of less than 1 nmol/L and more than 1000-fold selectivity against other phosphodiesterases. Tritiated PDM-042, [3H]PDM-042, had high affinity for membranes prepared from rat striatum with aKdvalue of 8.5 nmol/L. The specific binding of [3H]PDM-042 was displaced in a concentration-dependent manner by PDM-042 and another structurally unrelated PDE10A inhibitor, MP-10. In rat studies, PDM-042 showed excellent brain penetration (striatum/plasma ratio = 6.3), occupancy rate (86.6% at a dose of 3 mg/kg), and good oral bioavailability (33%). These data indicate that PDM-042 is a potent, selective, orally active, and brain-penetrable PDE10A inhibitor. In behavioral studies using rat models relevant to schizophrenia, PDM-042 significantly antagonized MK-801-induced hyperlocomotion (0.1-0.3 mg/kg) without affecting spontaneous locomotor activity and attenuated the conditioned avoidance response (CAR) (0.3-1 mg/kg). In tests for adverse effects, PDM-042 had a minimal effect on catalepsy, even at a much higher dose (10 mg/kg) than the minimal effective dose (0.3 mg/kg) in the CAR. Furthermore, PDM-042 had no effect on prolactin release or glucose elevation up to 3 mg/kg, while risperidone increased prolactin release and olanzapine enhanced glucose levels at doses near their efficacious ones in the CAR. Our results suggest that PDM-042 is a good pharmacological tool that can be used to investigate the role of PDE10A and may have therapeutic potential for the treatment of schizophrenia.
authors.affiliation: Biology Laboratory Discovery Research Mochida Pharmaceutical Co., Ltd Shizuoka Japan.
authors.forename: Keita
authors.initials: K
authors.lastname: Arakawa
authors.affiliation: Biology Laboratory Discovery Research Mochida Pharmaceutical Co., Ltd Shizuoka Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Maehara
authors.affiliation: Biology Laboratory Discovery Research Mochida Pharmaceutical Co., Ltd Shizuoka Japan.
authors.forename: Natsuko
authors.initials: N
authors.lastname: Yuge
authors.affiliation: Medicinal Chemistry Laboratory Discovery Research Mochida Pharmaceutical Co., Ltd. Shizuoka Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Ishikawa
authors.affiliation: Medicinal Chemistry Laboratory Discovery Research Mochida Pharmaceutical Co., Ltd. Shizuoka Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Miyazaki
authors.affiliation: Pharmacokinetics and Safety Laboratory Discovery Research Mochida Pharmaceutical Co., Ltd. Shizuoka Japan.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Naba
authors.affiliation: Biology Laboratory Discovery Research Mochida Pharmaceutical Co., Ltd Shizuoka Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kato
authors.affiliation: Head of Discovery Research Discovery Research Mochida Pharmaceutical Co., Ltd. Shizuoka Japan.
authors.forename: Kazunari
authors.initials: K
authors.lastname: Nakao
keywords: Antipsychotics; PDE10A; PDM‐042; catalepsy; occupancy; schizophrenia