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 IC 50 values 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 a K d value 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.

No abstract

Aims Recently, we identified a novel orexin 2 (OX 2 ) receptor antagonist, SDM‐878 (2‐(3‐(2‐(1 H ‐pyrazol‐1‐yl)nicotinoyl)‐3,8‐diazabicyclo[3.2.1]octan‐8‐yl)‐3‐methoxyisonicotinonitrile). The purpose of the present study is to characterize the in vitro and in vivo pharmacological effects of SDM‐878. Methods The in vitro potency and selectivity of SDM‐878 were examined in CHO cells that exhibit stable expression of human orexin 1 (OX 1 ), human orexin 2 (OX 2 ), rat OX 1 , and rat OX 2 receptors. Then, the plasma half‐life, oral bioavailability, and brain penetration of SDM‐878 were examined in rats. The in vivo effect of SDM‐878 in rats was tested using electroencephalography (EEG). The target engagement of SDM‐878 in the rat brain was examined using the antagonistic effect against hyperlocomotion caused by the intracerebroventricular administration of the OX 2 receptor agonist, ADL‐OXB ([Ala 11 , d‐Leu 15 ]‐orexin B). Results SDM‐878 showed potent inhibitory activities for human and rat OX 2 receptors with IC values of 10.6 and 8.8 nM, respectively, and approximately 1000‐fold selectivity against the OX 1 receptor. In rat studies, SDM‐878 exhibited a relatively short half‐life in plasma, oral bioavailability, and good brain penetration. These data indicate that SDM‐878 is a potent, selective, orally active, and brain‐penetrable OX 2 receptor antagonist. In behavioral studies using rats, SDM‐878 (100 mg/kg) antagonized hyperlocomotion caused by intracerebroventricular administration of ADL‐OXB. SDM‐878 exhibited a potent sleep‐promoting effect at the same dose (100 mg/kg) in a rat EEG study. Conclusion Our results suggest that SDM‐878 is likely to be a good pharmacological tool for investigating the role of the OX 2 receptor and may have therapeutic potential for the treatment of insomnia.

During treatment with protein therapeutics, such as monoclonal antibodies, the development of anti-drug antibodies is a serious side-effect of modern pharmacology. Anti-drug antibodies are produced as the number and exposure to therapeutic proteins increase. In this context, less immunogenic responses could diminish these noxious effects. Biophysical characterization of antigens, that is size, chemical composition, physical form, and degrability, are known to influence the outcome of immune responses. Here, using chemical modification, we have prepared oligomers of hen egg lysozyme (HEL), 3- to 5-mer, as a typical antigen in immunology and evaluated the efficacy as a tolerogen in HEL-specific antibody responses. Our results clearly demonstrated that pre-exposed the HEL-oligomers into mice effectively suppressed HEL-specific IgG responses regardless of the cross-linking mode. Therefore, the oligomerization is a method to induce tolerogenicity of proteins and may emerge as a promising strategy to control the production of undesirable anti-protein drug antibodies.