Discovery of a potent glucokinase activator with a favorable liver and pancreas distribution pattern for the treatment of type 2 diabetes mellitus.

Glucokinase (GK) is an enzyme that plays an important role as a glucose sensor while maintaining whole body glucose homeostasis. Allosteric activators of GK (GKAs) have the potential to treat type 2 diabetes mellitus. To identify novel GKAs, a series of compounds based on a thiophenyl-pyrrolidine scaffold were designed and synthesized. In this series, compound 38 was found to inhibit glucose excursion in an oral glucose tolerance test (OGTT) in mice. Optimization of 38 using a zwitterion approach led to the identification of the novel GKA 59. GKA 59 exhibited potent blood glucose control in the OGTT test as well as a favorable safety profile. Owing to low pancreatic distribution, compound 59 primarily activates GK in the liver. This characteristic could overcome limitations of other GKAs, such as hypoglycemia, increased plasma triglycerides, and loss of efficacy.

Prevalence and characteristics of human parechovirus and enterovirus infection in febrile infants.

BACKGROUND: Human parechovirus (HPeV) and human non-polio enterovirus (EV) are important causes of fever without source (FWS) in young infants. Their prevalence and clinical characteristics are largely unknown in Asian countries. This study was conducted to elucidate the epidemiology and clinical characteristics of HPeV and EV infection in febrile young infants in Japan. METHODS: During February 2010-August 2015, we obtained 53 stool, 44 throat swab, and 20 cerebrospinal fluid samples from 56 infants (<3 months) with FWS at a single hospital. To each sample, we applied reverse transcription-polymerase chain reaction for HPeV and EV. We compared the clinical characteristics of HPeV and EV patients. RESULTS: HPeV was detected in 11 and EV in 17 patients. HPeV was detected during July-September. HPeV patients, compared with EV patients, had lower age (32 vs 47 days; P = n.s.), higher prevalence of exclusive breast-feeding (81.8 vs 29.4%; P = 0.024), and lower prevalence of sick contacts (36.4 vs 88.2%; P = 0.010). More HPeV than EV patients met the systemic inflammatory response syndrome criteria (90.9 vs 52.9%; P = 0.049). In the HPeV group, leukopenia, thrombopenia, and elevated deviation enzyme were observed, although the prevalence of abnormal cerebrospinal fluid was significantly lower than in the EV group. HPeV patients had longer hospital stay (7 vs 5 days; P = 0.025). CONCLUSION: HPeV and EV are important causal viruses of FWS. Characteristic clinical pictures exist in these virus infections, but further research is needed to accumulate more cases to produce a comprehensive picture of these virus infections.

Synthesis and pharmacological profile of a new selective G protein-coupled receptor 119 agonist; 6-((2-fluoro-3-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)propyl)amino)-2,3-dihydro-1H-inden-1-one.

6-((2-Fluoro-3-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)propyl)amino)-2,3-dihydro-1H-inden-1-one is a potent drug-like G protein-coupled receptor 119 (GPR119) agonist. It is hoped that this compound would be instrumental in probing the pharmacological potential of GPR119 agonists.

Synthesis and SAR studies of bicyclic amine series GPR119 agonists.

We disclosed a novel series of G-protein coupled receptor 119 (GPR119) agonists based on a bicyclic amine scaffold. Through the optimization of hit compound 1, we discovered that the basic nitrogen atom of bicyclic amine played an important role in GPR119 agonist activity expression and that an indanone in various bicyclic rings was suitable in this series of compounds. The indanone derivative 2 showed the effect of plasma glucose control in oGTT and scGTT in the rodent model.

Collaborative work on evaluation of ovarian toxicity. 15) Two- or four-week repeated-dose studies and fertility study of bromocriptine in female rats.

The main focus of this study is to determine the optimal administration period concerning toxic effects on ovarian morphological changes in a repeated-dose toxicity study. To assess morphological and functional changes induced in the ovary by bromocriptine, the compound was administered to female rats at dose levels of 0, 0.08, 0.4 and 2 mg/kg for the 2- or 4-week repeated-dose toxicity study, and for the female fertility study from 2 weeks prior to mating to day 7 of gestation. In the 2-week repeated-dose toxicity study, increase of ovarian weights was observed at 2 mg/kg. In the 4-week repeated-dose toxicity study, ovarian weights were increased at 0.4 and 2 mg/kg. The number of corpora luteum was increased in the 0.4 and 2 mg/kg groups of the 2- and 4-week repeated-dose toxicity studies by histopathological examination of the ovaries. Bromocriptine did not affect estrous cyclicity in 2- and 4-week repeated dosing. In the female fertility study, although animals in any groups mated successfully, no females in 0.4 and 2 mg/kg groups were pregnant. There were no adverse effects on reproductive performance in the 0.08 mg/kg group. Based on these findings, the histopathological changes in the ovary are considered important parameters for evaluation of drugs including ovarian damage. We conclude that a 2-week administration period is sufficient to detect ovarian toxicity of bromocriptine in a repeated-dose toxicity study.

Effects of glutamate-related drugs on marble-burying behavior in mice: implications for obsessive-compulsive disorder.

Clinical evidence demonstrates altered glutamatergic neurotransmission in patients suffering from obsessive-compulsive disorder (OCD). We examined the effects of glutamate-related drugs on marble-burying behavior, which is an animal model of OCD. The uncompetitive N-methyl-d-aspartate (NMDA) antagonists memantine (10 mg/kg, i.p.) and amantadine (30 mg/kg, i.p.) significantly inhibited marble-burying behavior without affecting locomotor activity in mice. Similarly, the uncompetitive NMDA receptor antagonist 5R,10S-(+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine hydrogen maleate (MK-801, 0.3 mg/kg, i.p.) inhibited marble-burying behavior. However, MK-801 at the same dose markedly increased locomotor activity. By contrast, the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor antagonist 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide (NBQX) and the glutamate release inhibitor riluzole showed no effect on marble-burying behavior and significant suppression of locomotor activity. MK-801 (0.3 mg/kg, i.p.) and memantine (10 mg/kg, i.p.) significantly disrupted prepulse inhibition as an operational measure of sensorimotor gating. By contrast, amantadine (30 mg/kg, i.p.) did not affect prepulse inhibition. These findings suggest that amantadine could be a useful drug for the treatment of OCD.

Involvement of the sigma1 receptor in inhibiting activity of fluvoxamine on marble-burying behavior: comparison with paroxetine.

In the present study, we examined the involvement of the sigma1 receptor in the inhibitory effect of the selective serotonin reuptake inhibitor (SSRI) fluvoxamine, compared with that of paroxetine, on marble-burying behavior, which is an animal model of obsessive-compulsive disorder. Sigma1 receptor agonists (+)-SKF 10047 and PRE-084 significantly inhibited marble-burying behavior. Sigma receptor antagonist BD 1047 and selective sigma1 receptor antagonist BD 1063 significantly attenuated the inhibition of marble-burying behavior by fluvoxamine. In contrast, selective sigma2 receptor antagonist SM-21 failed to affect the inhibition of marble-burying behavior by fluvoxamine. On the other hand, BD 1047 and BD 1063 had no effect on the inhibition of marble-burying behavior by paroxetine. These observations show that activation of the sigma1 receptor is a necessary component in the inhibitory effect of fluvoxamine on marble-burying behavior, and that the mechanism of its action is clearly different from that of paroxetine.

Impaired social interaction and reduced anxiety-related behavior in vasopressin V1a receptor knockout mice.

The arginine vasopressin (AVP) system plays an important role in social behavior. Autism, with its hallmark disturbances in social behavior, has been associated with the V1a receptor (V1aR) gene. Furthermore, impairments of social function are often observed in symptoms of schizophrenia. Subchronic phencyclidine (PCP) produces behaviors relating to certain aspects of schizophrenic symptoms such as impairing social interaction in animals and it reduces the density of V1aR binding sites in several brain regions. Here, we report that V1aR knockout (KO) mice exhibited impairment of social behavior in a social interaction test, and showed reduced anxiety-related behavior in elevated plus-maze and marble-burying behavior tests. Given the current findings, the V1aR may be involved in the regulation of social interaction, and V1aR KO mice could be used as an animal model of psychiatric disorders associated with social behavior deficits, such as autism and schizophrenia.

Perospirone, a novel antipsychotic drug, inhibits marble-burying behavior via 5-HT1A receptor in mice: implications for obsessive-compulsive disorder.

Perospirone is a novel atypical antipsychotic drug with dopamine (DA) D(2)- and serotonin (5-hydroxytryptamine, 5-HT) 5-HT(2A)-receptor antagonist, and 5-HT(1A)-receptor agonist properties. In the present study, we examined the effect of perospirone on marble-burying behavior, which has been considered an animal model of obsessive-compulsive disorder (OCD), compared with the effects of other antipsychotics such as haloperidol and risperidone. Perospirone at a dose of 10 mg/kg (p.o.) inhibited marble-burying behavior without affecting the locomotor activity in mice. On the other hand, haloperidol (0.1 mg/kg, i.p.) and risperidone (1 mg/kg, p.o.) showed significant suppression of locomotor activity at the dose that inhibited marble-burying behavior. Furthermore, the inhibition of marble-burying behavior by perospirone was antagonized by WAY100135 (10 mg/kg, i.p.), a selective 5-HT(1A)-receptor antagonist. WAY100135 at the same dose also antagonized the inhibition of marble-burying behavior by 8-OH-DPAT (3 mg/kg, i.p.), a selective 5-HT(1A)-receptor agonist. These findings suggest that perospirone may exhibit anti-OCD activity in clinical use and that 5-HT(1A)-receptor agonistic activity may be involved in the inhibition of marble-burying behavior by perospirone.