Emotional and motivational disorders in adults are often considered to be the result of altered neurodevelopment. Clinical and experimental data provide evidence that serine protease dipeptidyl peptidase-IV (DPP-IV, E...Emotional and motivational disorders in adults are often considered to be the result of altered neurodevelopment. Clinical and experimental data provide evidence that serine protease dipeptidyl peptidase-IV (DPP-IV, EC 3.4.14.5) is involved in the pathophysiology of psycho-emotional disorders. Recently, we have shown that adolescent and adult rats exhibit an increase in anxiety and depression-related behaviors after neonatal administration of a synthetic non-competitive inhibitor of DPP-IV, methionyl-2(S)-cyano-pyrrolidine. In the present study, we tested the effects of two competitive, selective DPP-IV inhibitors, sitagliptin (4 mg/kg) and diprotin A (2 mg/kg), administered at postnatal days 5 - 18 on the emotional and motivational behavior of adolescent and adult rats. We observed increased anxiety in one-month-old diprotin A- or sitagliptin-treated rats in the elevated plus maze;diprotin A also enhanced the animals’ anxiety score using a ranked scale for evaluating anxiety and phobias. In the sucrose consumption and preference test, depressive-like behavior was pronounced in both the diprotin A- and sitagliptin-treated one-month-old animals, while only the diprotin A-treated rats exhibited a decrease in sucrose consumption at the age of 2 months. The diprotin A-treated rats also demonstrated behavioral despair and decreased activity in the forced swimming test within 1 - 3 months of age. Increased aggression was observed in 1 - 3-month-old diprotin A-treated rats and in two-month-old sitagliptin-treated rats. These findings support the hypothesis that DPP-IV is involved in the genesis of emotional and motivational disorders. Additionally, the results show that diprotin А impairs the adolescent and adult rats’ behavior more significantly than sitagliptin when the animals were treated with the DPP-IV inhibitors in the early postnatal period.展开更多
E3024 (3-but-2-ynyl-5-methyl-2-piperazin-1-yl-3,5-dihydro-4H-imidazo[4,5-d]pyridazin-4-one tosylate) is a dipeptidyl peptidase-IV (DPP-IV) inhibitor that was expected to be an antidiabetic agent. Its safety, tolerabil...E3024 (3-but-2-ynyl-5-methyl-2-piperazin-1-yl-3,5-dihydro-4H-imidazo[4,5-d]pyridazin-4-one tosylate) is a dipeptidyl peptidase-IV (DPP-IV) inhibitor that was expected to be an antidiabetic agent. Its safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) were investigated in a randomized, double-blind, placebo-controlled, ascending single-dose study in 48 healthy Japanese male subjects. Fasted subjects were orally administered E3024 (5, 10, 20, 40, or 80 mg) or placebo. E3024 was rapidly absorbed, with tmax values ranging between 0.33 and 3 h after dosing. The mean t1/2 ranged from 5.34 to 11.68 h. AUC0-inf and Cmax increased dose-proportionately. PK-PD relationship of E3024 was evaluated by using an Imax model, indicating that plasma E3024 concentrations and inhibitory effects of plasma DPP-IV activity were well correlated. The IC50 value was calculated as 33.7 ng/mL, which was consistent with in vitro data. Thus, E3024 showed a good PK profile and inhibited DPP-IV dose-dependently. Of 30 subjects administered E3024, 12 (40%) experienced adverse events (AEs). Dose escalation to 160 mg was abandoned owing to undesired subjective/objective findings in 4 of 6 subjects receiving 40 mg and 5 of 6 subjects receiving 80 mg. The most prominent AE was rash, but there were no serious AEs or deaths. The maximum tolerated dose was considered to be 20 mg. We hypothesized that histamine was a cause of the rash induction, and examined blood histamine levels of normal Fischer rats treated with E3024. Blood histamine levels were increased significantly by E3024 at 500 mg/kg (p < 0.001), but not by vildagliptin or valine-pyrrolidide (DPP-IV inhibitors) at the same dose. No blood histamine increases were observed in genetically mast cell-deficient Ws/Ws rats treated with E3024 at 500 mg/kg. In in vitro assays, E3024 induced histamine release from normal rat peritoneal mast cells in a concentration-dependent manner, but not from basophils. The structure-activity relationship study suggested that a piperazine group N-linked to the 2-position of the 5,6-membered fused heterocyclic rings was a key structural element for triggering histamine release.展开更多
Describing a reported case of acute pancreatitis in a patient receiving sitagliptin. We present the biochemical and findings of a 60 year-old male who presented with severe abdominal pain and was found to have acute p...Describing a reported case of acute pancreatitis in a patient receiving sitagliptin. We present the biochemical and findings of a 60 year-old male who presented with severe abdominal pain and was found to have acute pancreatitis. This occurred one month after the commencement of sitagliptin, a dipeptidyl peptidase IV inhibitor, for the treatment of uncontrolled type 2 diabetes. Results: Pancreatic enzymes were elevated (i.e. amylase 204, lipase: 525.3) with a normal liver function test and a normal lipid profile. Ultrasound abdomen was unremarkable. In the absence of an identifiable cause for the patient’s pancreatitis, sitagliptin was considered a potential trigger and on ceasing this agent, the patient recovered from his condition. Conclusion: Incretin-based therapy is an effective line in the treatment of type 2 diabetes mellitus. FDA issued a warning letters to the drug company because of emerging reports of acute pancreatitis in patients receiving sitagliptin. This is unfortunately not the first reported case of acute pancreatitis in a patient receiving sitagliptin and it supports the possibility that acute pancreatitis may be the effect of incretin-based therapy.展开更多
The present work was focused on the study of the three-dimensional(3D)structural.requirements for the highly potent bioactivity of dipeptidyl peptidase(DPP)IV's inhibitor.At first,molecular dynamic and mechanic(MD...The present work was focused on the study of the three-dimensional(3D)structural.requirements for the highly potent bioactivity of dipeptidyl peptidase(DPP)IV's inhibitor.At first,molecular dynamic and mechanic(MDMM)simulations were performed to research the conformations of the potent DPP IV's inhibitor 5-(aminomethyl)-6-(2,4-dichlorophenyl)-2-(3,5-dimethoxy-phenyl)pyrimidin-4-amine.Using the MD/MM-determined molecular conformers as templates,the 3D quantitative structure activity relationship(QSAR)studies were carried out based on a set of arylmethylamine DPP IV inhibitors with the comparative molecular feld analysis(CoMFA)approach.The best 3D-QSAR model was constructed with good statistic values of r^(2)_(cv) and R^(2) using PLS analyses(CoMFA:r^(2)_(cv)=0.660,R^(2)=0.953).The generated 3D-QSAR model was proved to be reliable by internal and external validations.Docking studies were further performed to analyze the interaction mode between the highly potent or low potent arylmethylamine derivatives and DPP IV.Our flexible docking results also confirmed the possible bioactive conformation obtained from the 3D-QSA R model,of arylmethylamine-based DPP IV inhibitors.The 3D-QSAR model may provide information of pharmacophoric features for further design and optimization of new scaffold compounds with high inhibitory activity to DP IV.展开更多
文摘Emotional and motivational disorders in adults are often considered to be the result of altered neurodevelopment. Clinical and experimental data provide evidence that serine protease dipeptidyl peptidase-IV (DPP-IV, EC 3.4.14.5) is involved in the pathophysiology of psycho-emotional disorders. Recently, we have shown that adolescent and adult rats exhibit an increase in anxiety and depression-related behaviors after neonatal administration of a synthetic non-competitive inhibitor of DPP-IV, methionyl-2(S)-cyano-pyrrolidine. In the present study, we tested the effects of two competitive, selective DPP-IV inhibitors, sitagliptin (4 mg/kg) and diprotin A (2 mg/kg), administered at postnatal days 5 - 18 on the emotional and motivational behavior of adolescent and adult rats. We observed increased anxiety in one-month-old diprotin A- or sitagliptin-treated rats in the elevated plus maze;diprotin A also enhanced the animals’ anxiety score using a ranked scale for evaluating anxiety and phobias. In the sucrose consumption and preference test, depressive-like behavior was pronounced in both the diprotin A- and sitagliptin-treated one-month-old animals, while only the diprotin A-treated rats exhibited a decrease in sucrose consumption at the age of 2 months. The diprotin A-treated rats also demonstrated behavioral despair and decreased activity in the forced swimming test within 1 - 3 months of age. Increased aggression was observed in 1 - 3-month-old diprotin A-treated rats and in two-month-old sitagliptin-treated rats. These findings support the hypothesis that DPP-IV is involved in the genesis of emotional and motivational disorders. Additionally, the results show that diprotin А impairs the adolescent and adult rats’ behavior more significantly than sitagliptin when the animals were treated with the DPP-IV inhibitors in the early postnatal period.
文摘E3024 (3-but-2-ynyl-5-methyl-2-piperazin-1-yl-3,5-dihydro-4H-imidazo[4,5-d]pyridazin-4-one tosylate) is a dipeptidyl peptidase-IV (DPP-IV) inhibitor that was expected to be an antidiabetic agent. Its safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) were investigated in a randomized, double-blind, placebo-controlled, ascending single-dose study in 48 healthy Japanese male subjects. Fasted subjects were orally administered E3024 (5, 10, 20, 40, or 80 mg) or placebo. E3024 was rapidly absorbed, with tmax values ranging between 0.33 and 3 h after dosing. The mean t1/2 ranged from 5.34 to 11.68 h. AUC0-inf and Cmax increased dose-proportionately. PK-PD relationship of E3024 was evaluated by using an Imax model, indicating that plasma E3024 concentrations and inhibitory effects of plasma DPP-IV activity were well correlated. The IC50 value was calculated as 33.7 ng/mL, which was consistent with in vitro data. Thus, E3024 showed a good PK profile and inhibited DPP-IV dose-dependently. Of 30 subjects administered E3024, 12 (40%) experienced adverse events (AEs). Dose escalation to 160 mg was abandoned owing to undesired subjective/objective findings in 4 of 6 subjects receiving 40 mg and 5 of 6 subjects receiving 80 mg. The most prominent AE was rash, but there were no serious AEs or deaths. The maximum tolerated dose was considered to be 20 mg. We hypothesized that histamine was a cause of the rash induction, and examined blood histamine levels of normal Fischer rats treated with E3024. Blood histamine levels were increased significantly by E3024 at 500 mg/kg (p < 0.001), but not by vildagliptin or valine-pyrrolidide (DPP-IV inhibitors) at the same dose. No blood histamine increases were observed in genetically mast cell-deficient Ws/Ws rats treated with E3024 at 500 mg/kg. In in vitro assays, E3024 induced histamine release from normal rat peritoneal mast cells in a concentration-dependent manner, but not from basophils. The structure-activity relationship study suggested that a piperazine group N-linked to the 2-position of the 5,6-membered fused heterocyclic rings was a key structural element for triggering histamine release.
文摘Describing a reported case of acute pancreatitis in a patient receiving sitagliptin. We present the biochemical and findings of a 60 year-old male who presented with severe abdominal pain and was found to have acute pancreatitis. This occurred one month after the commencement of sitagliptin, a dipeptidyl peptidase IV inhibitor, for the treatment of uncontrolled type 2 diabetes. Results: Pancreatic enzymes were elevated (i.e. amylase 204, lipase: 525.3) with a normal liver function test and a normal lipid profile. Ultrasound abdomen was unremarkable. In the absence of an identifiable cause for the patient’s pancreatitis, sitagliptin was considered a potential trigger and on ceasing this agent, the patient recovered from his condition. Conclusion: Incretin-based therapy is an effective line in the treatment of type 2 diabetes mellitus. FDA issued a warning letters to the drug company because of emerging reports of acute pancreatitis in patients receiving sitagliptin. This is unfortunately not the first reported case of acute pancreatitis in a patient receiving sitagliptin and it supports the possibility that acute pancreatitis may be the effect of incretin-based therapy.
基金The project is supported by grants from National Key Tech Project for Major Creation of New Drugs(2009ZX09501-003 to Jianzhong Chen)Science Foundation of Chinese University(2009QNA7024 to Jianzhong Chen)。
文摘The present work was focused on the study of the three-dimensional(3D)structural.requirements for the highly potent bioactivity of dipeptidyl peptidase(DPP)IV's inhibitor.At first,molecular dynamic and mechanic(MDMM)simulations were performed to research the conformations of the potent DPP IV's inhibitor 5-(aminomethyl)-6-(2,4-dichlorophenyl)-2-(3,5-dimethoxy-phenyl)pyrimidin-4-amine.Using the MD/MM-determined molecular conformers as templates,the 3D quantitative structure activity relationship(QSAR)studies were carried out based on a set of arylmethylamine DPP IV inhibitors with the comparative molecular feld analysis(CoMFA)approach.The best 3D-QSAR model was constructed with good statistic values of r^(2)_(cv) and R^(2) using PLS analyses(CoMFA:r^(2)_(cv)=0.660,R^(2)=0.953).The generated 3D-QSAR model was proved to be reliable by internal and external validations.Docking studies were further performed to analyze the interaction mode between the highly potent or low potent arylmethylamine derivatives and DPP IV.Our flexible docking results also confirmed the possible bioactive conformation obtained from the 3D-QSA R model,of arylmethylamine-based DPP IV inhibitors.The 3D-QSAR model may provide information of pharmacophoric features for further design and optimization of new scaffold compounds with high inhibitory activity to DP IV.
