Neuroprotective Effect of Thiazolidine-2,4-dione Derivatives on Memory Deficits and Neuropathological Symptoms of Dementia on a Scopolamine-Induced Alzheimer's Model in Adult Male Wistar Rats.

Alzheimer's disease (AD) is a neurodegenerative disorder associated with a decline in memory deficits and neuropathological diagnosis with loss of cholinergic neurons in the brains of older adults. Based on these facts and an increasing number of involved people worldwide, this investigation aimed to study the improvement of memory and cognitive impairments via an anticholinergic approach of thiazolidine-2,4-diones (TZDs) in the scopolamine-induced model of Alzheimer type in adult male Wistar rats (n = 40). The results indicated data analysis obtained from in vivo and in vitro tests for (E)-5-(3-hydroxybenzylidene)-3-(2-oxo-2-phenylethyl)thiazolidine-2,4-dione (TZ3O) (2 and 4 mg/kg) with the meta-hydroxy group and (E)-5-(4-methoxybenzylidene)-3-(2-oxo-2-phenylethyl)thiazolidine-2,4-dione (TZ4M) (2 and 3 mg/kg) with the para-methoxy group showed a neuroprotective effect. TZ3O and TZ4M alleviated the scopolamine-induced cognitive decline of the Alzheimer model in adult male Wistar rats. These initial and noteworthy results could be assumed as a starting point for the evolution of new anti-Alzheimer agents.

Evaluation of Teneligliptin a DPP4 Inhibitor in Terms of Efficacy and Safety with Respect to QT/QTc Prolongation in Patients with Type II Diabetes Mellitus (T2DM).

INTRODUCTION: Low risk of hypoglycemia and weight neutrality have increased the administration of dipeptidyl peptidase 4 (DPP-4) inhibitors in patients with T2DM in clinical practice. Currently Teneligliptin is prescribed as a second or third add on to the standard treatment with other classes of oral hypoglycemic agents (OHAs) to achieve targeted glycemic control in type 2 DM patients. METHODS: An open label, interventional, single arm, 12 weeks study was conducted on160 patients with type 2 DM at MGM Medical College, Aurangabad with Teneligliptin 20 mg once a day as add on to the ongoing standard treatment with other classes of OHAs. Changes in glycemia parameters like FBS, PPBS HbA1C, body weight were assessed and twelve lead ECG was recorded with safety assessment at baseline and follow-up visits.. The QTc was calculated by using the Bazett's formula (QTc=QT/√RR).The study was conducted with an objective to assess efficacy and safety of Teneligliptin with respect to QT/QTc prolongation in patients with T2DM. RESULTS: A significant reduction was seen in the glycemic parameters like FBS, PPBS HbA1C from the baseline values (P<0.001) but no significant change in the QT interval (P=0.9563) and QTc interval (P=0.5594) from the baseline to the end of study at12 weeks. CONCLUSION: Tenelegliptin is a promising new drug to help to achieve targeted glycemic control in patients with T2DM without prolonging the QT/QTc interval.

Whether Immunostimulants Are Effective in Susceptible Children Suffering From Recurrent Respiratory Tract Infections: A Modeling Analysis Based on Literature Aggregate Data.

Immunostimulants are gradually being used in the prevention and treatment of recurrent respiratory tract infections in susceptible children, but their drug effects have not been quantified. The purpose of this study was to confirm the efficacy of immunostimulants in the prevention and treatment of recurrent respiratory tract infections in susceptible children. A model-based meta-analysis was used to describe the time course of placebo and immunostimulants in the prevention of respiratory tract infections in children. The cumulative number of respiratory tract infections was used as an indicator of efficacy. A meta-analysis was used to analyze the incidence of drug-related adverse events. Fourteen articles with 2400 pediatric subjects were finally included in the analysis. The results showed that the cumulative number of respiratory tract infections increased linearly with time, with the incidence of respiratory tract infections in the placebo group being 0.65 (95% confidence interval [CI], 0.55-0.75) per month. OM-85 BV and pidotimod reduced the incidence of respiratory tract infections by 0.21 (95%CI, 0.16-0.26) and 0.19 (95%CI, 0.17-0.21) compared to placebo per month, respectively. Pidotimod and OM-85 BV can effectively reduce the incidence of respiratory tract infections in susceptible children, with no significant increase in the incidence of drug-related adverse events when compared with placebo (risk ratio values were 1.07 [95%CI, 0.66-1.71] and 1.31 [95%CI, 0.54-3.19], respectively). This study provides quantitative support for the application of immunostimulants for the prevention of recurrent respiratory tract infections in children.

Pidotimod increases inflammation in wounded zebrafish embryos.

Pidotimod (PDT) is a synthetic dipeptide molecule which can improve immune responses in mice and humans, protecting hosts from infection. However, the exact mechanism of protection remains ill-defined. The effect of pidotimod has not yet been investigated in the inflammatory response of zebrafish. In this study, we used tail wound and infection models of zebrafish to study the effect of PDT on inflammation. We found that zebrafish larvae were sensitive to PDT immersion causing toxicity at doses above 50 µg/mL. The tail wound assay showed that PDT increased the recruitment of neutrophils and macrophages to the wound site and promoted the transcription of the pro-inflammatory cytokine il1b. However, we did not observe protection of uropathogenic Escherichia coli or Mycobacterium marinum infected zebrafish larvae following PDT treatment. This study provides a new platform for PDT research, which is worthy of further research to identify further effects of PDT therapy.

Effect of Teneligliptin versus Sulfonylurea on Major Adverse Cardiovascular Outcomes in People with Type 2 Diabetes Mellitus: A Real-World Study in Korea.

BACKGROUND: Results regarding the cardiovascular (CV) effects of dipeptidyl peptidase-4 (DPP-4) inhibitors are inconsistent. This study aimed to assess the effects of teneligliptin, a DPP-4 inhibitor, on the risk of major CV outcomes in type 2 diabetes mellitus (T2DM) patients compared to sulfonylurea. METHODS: From January 1, 2015 to December 31, 2017, we conducted a retrospective cohort study using the Korean National Health Insurance Service database. A total of 6,682 T2DM patients who were newly prescribed DPP-4 inhibitors or sulfonylurea were selected and matched in a 1:1 ratio by propensity score. The hazard ratios (HRs) for all-cause mortality, hospitalization for heart failure (HHF), all-cause mortality or HHF, myocardial infarction (MI), stroke, and hypoglycemia were assessed. RESULTS: During 641 days of follow-up, the use of teneligliptin was not associated with an increased risk of all-cause mortality (HR, 1.00; 95% confidence interval [CI], 0.85 to 1.19), HHF (HR, 0.99; 95% CI, 0.86 to 1.14), all-cause mortality or HHF (HR, 1.02; 95% CI, 0.90 to 1.14), MI (HR, 0.90; 95% CI, 0.68 to 1.20), and stroke (HR, 1.00; 95% CI, 0.86 to 1.17) compared to the use of sulfonylurea. However, it was associated with a significantly lower risk of hypoglycemia (HR, 0.68; 95% CI, 0.49 to 0.94) compared to sulfonylurea therapy. CONCLUSION: Among T2DM patients, teneligliptin therapy was not associated with an increased risk of CV events including HHF, but was associated with a lower risk of hypoglycemia compared to sulfonylurea therapy.

Extending the investigation of 4-thiazolidinone derivatives as potential multi-target ligands of enzymes involved in diabetes mellitus and its long-term complications: A study with pancreatic α-amylase.

Diabetes mellitus is a multifactorial disease, which is frequently complicated by the development of hyperglycaemia-induced chronic complications. The therapy of diabetes mellitus often requires combinations of two or more drugs in order both to control glycaemic levels and to prevent hyperglycaemia-induced dangerous affairs. The application of multi-target agents, which are able to control simultaneously several pathogenic mechanisms, represents a useful alternative and, in fact, their discovery is a pursued aim of the research. Some (5-arylidene-4-oxo-2-thioxothiazolidin-3-yl)acetic acids, which we had previously reported as inhibitors of selected enzymes critically implicated in diabetes mellitus, were tested against pancreatic α-amylase and intestinal α-glucosidase. These enzymes catalyse the hydrolysis of dietary oligo- and polysaccharides into monosaccharides and, consequently, are responsible for postprandial hyperglycaemia; therefore, their inhibition is one of the possible strategies to control glycaemic levels in diabetes mellitus. In addition, we investigated the aggregation tendency of the tested compounds, through direct and indirect methods, in order to evaluate the mechanism of their multiple action and discover if aggregation may contribute to the inhibition of the target enzymes. Overall, compounds 1, 3 and 4 exhibited the most favourable profile since they were shown to act as multi-target inhibitors of enzymes involved in pathways related to diabetes mellitus, without producing aggregates even at high micromolar concentrations and, therefore, can be promising agents for further developments.

Long-Term Safety and Efficacy of Teneligliptin in Elderly Patients with Type 2 Diabetes: Subgroup Analysis of a 3-Year Post-Marketing Surveillance in Japan.

INTRODUCTION: Teneligliptin, a dipeptidyl peptidase 4 inhibitor, was approved for the treatment of type 2 diabetes mellitus (T2DM) in Japan in 2012. However, clinical trials of teneligliptin involved limited numbers of elderly patients. Therefore, we investigated the safety and efficacy of teneligliptin in elderly patients with T2DM. METHODS: This 3-year follow-up RUBY surveillance registered patients with T2DM who started treatment with teneligliptin between May 2013 and February 2015 in Japan. Collected data included demographics, treatments, adverse drug reactions (ADRs), and laboratory variables. Data were analysed for patients in three age subgroups (< 65, ≥ 65 to < 75, or ≥ 75 years old). Safety was assessed as the incidence of ADRs and efficacy was assessed in terms of glycaemic control, for up to 3 years. RESULTS: The ADRs and serious ADRs occurred in 3.35% and 0.65% of 4596 patients aged < 65 years, in 4.42% and 1.22% of 3371 patients aged ≥ 65 to < 75 years, and in 3.99% and 1.69% of 2729 patients aged ≥ 75 years. The most common ADRs in patients aged ≥ 65 to < 75 years and ≥ 75 years were gastrointestinal disorders, but the incidence of these ADRs did not show an age-dependent increase. Hypoglycaemia occurred in 0.24%, 0.56%, and 0.29% of patients in each age subgroup, respectively. The least-squares mean changes in glycosylated haemoglobin (HbA1c) adjusted for baseline were - 0.66 ± 0.02% (n = 2177), - 0.72 ± 0.02% (n = 1689), and - 0.77 ± 0.03% (n = 1161) at 3 years. CONCLUSION: There was no clear difference in the number of ADRs among the three age subgroups, although the incidence of serious ADRs was higher in elderly patients than in patients aged < 65 years. We found no additional safety or efficacy concerns among elderly patients beyond those already described in the package insert. The present results support the use of teneligliptin in elderly patients with T2DM in real-world clinical practice. TRIAL REGISTRATION: Japic Clinical Trials Information identifier, Japic CTI-153047.

Teneligliptin is an oral drug taken once daily to manage blood glucose levels in people with type 2 diabetes. A number of studies of teneligliptin have investigated its safety and efficacy, but these studies included limited numbers of elderly people, aged 75 years or older. Following the approval of teneligliptin in Japan, post-marketing surveillance was started to monitor its safety and efficacy when prescribed by doctors to people in actual clinical practice. We analysed data from the surveillance to check if the safety and efficacy of teneligliptin differ in younger and older people separately. We found that there was no clear difference in the number of adverse drug reactions among three age subgroups: < 65 years, ≥ 65 to < 75 years, or ≥ 75 years, although the incidence of serious adverse drug reactions was higher in elderly patients than in patients aged < 65 years. Treatment with teneligliptin also lowered blood glucose levels in all three age subgroups, and the changes were maintained for up to 3 years in many individuals in each age subgroup. We found no additional safety or efficacy concerns among elderly patients beyond those already described in the package insert. The present results support the use of teneligliptin for the treatment of elderly patients with type 2 diabetes mellitus in real-world clinical practice.

Review on Chemistry, Analysis and Pharmacology of Teneligliptin: A Novel DPP-4 Inhibitor.

This article provides comprehensive and collective facts about teneligliptin. Teneligliptin is a dipeptide peptidase-4 (DPP-4) inhibitor that belongs to the third generation, used in the management of type 2 diabetes. It inhibits human DPP-4 enzyme activity. This drug falls under class 3; it interacts with S1, S2, and S2E extensive sub-sites. Teneligliptin and its metabolites are mainly determined in the human plasma matrix by hyphenated chromatographic methods. These developed methods could be foreseen for their clinical applications. Moreover, the stress degradation studies of Teneligliptin under different stress conditions provide an insight into degradation pathways and help in the elucidation of the structure of the degradation products by liquid mass spectroscopy. These methods are also used for routine quality control analysis of teneligliptin in pharmaceutical dosage forms.

Multicenter prospective observational study of teneligliptin, a selective dipeptidyl peptidase-4 inhibitor, in patients with poorly controlled type 2 diabetes: Focus on glycemic control, hypotensive effect, and safety Chikushi Anti-Diabetes Mellitus Trial-Teneligliptin (CHAT-T).

Objective: We purpose to confirm the effect of teneligliptin (Tenelia), a selective dipeptidyl peptidase-4 (DPP-4) inhibitor, on glycemic control and non-glucose risk factors for macroangiopathy, including blood pressure, lipid metabolism, and body weight.Methods: In a prospective, multicenter, open-label, observational study, teneligliptin (20 mg/day) was administered to type 2 diabetic patients with poor glycemic control (HbA1c ≥ 6.5% to <10%) at our hospitals. The safety of teneligliptin and its impact on blood glucose, blood pressure, and the lipid profile were assessed after administration for 3 and 6 months.Results: One hundred and sixty-two patients were enrolled between February 2014 and August 2015. HbA1c was 7.6% at baseline and showed significant reduction to 7.1% after 3 months of treatment and to 6.9% after 6 months (both p < 0.01). Patients with poorly controlled hypertension (systolic blood pressure [SBP] ≥130 mmHg and/or diastolic blood pressure [DBP] ≥80 mmHg) at study initiation were extracted to investigate the effect of teneligliptin on blood pressure. SBP showed a significant decrease from 141.2 ± 9.8 mmHg at baseline to 131.1 ± 14.3 mmHg after 3 months and 133.9 ± 11.5 mmHg after 6 months (both p < 0.001). DBP also decreased significantly from 85.8 ± 5.7 mmHg at baseline to 78.4 ± 10.0 mmHg after 3 months and 79.7 ± 10.1 mmHg after 6 months (both p < 0.001). Adverse events were pruritus in four patients, and cerebral infarction was reported as a cerebrovascular event in one patient.Conclusions: Teneligliptin therapy was safe and improved glycemic control irrespective of baseline HbA1c. Blood pressure was also improved in patients with concomitant hypertension.

Long-Term, Real-World Safety and Efficacy of Teneligliptin: A Post-Marketing Surveillance of More Than 10,000 Patients with Type 2 Diabetes in Japan.

INTRODUCTION: Teneligliptin is a dipeptidyl peptidase 4 inhibitor that was approved for the treatment of type 2 diabetes mellitus (T2DM) in Japan in 2012. We performed a long-term post-marketing surveillance (RUBY) to obtain real-world evidence regarding the safety and efficacy of teneligliptin in Japan. METHODS: This 3-year follow-up RUBY surveillance registered patients with T2DM who started treatment with teneligliptin between May 2013 and February 2015 in Japan. Collected data included demographics, treatments, adverse drug reactions (ADRs) and laboratory variables. Data were evaluated in all patients and in patients divided according to baseline renal function across categories of estimated glomerular filtration rate (G1-G5) and dialysis. Safety was assessed as the incidence of ADRs and efficacy was assessed in terms of glycaemic control, for up to 3 years. RESULTS: Of 11,677 patients registered, 10,696 and 10,249 were evaluable for safety and efficacy analyses, respectively. The median duration of exposure was 1096 days. ADRs occurred in 412 patients (3.85%) and were serious in 117 patients (1.09%). The most frequent ADR class was gastrointestinal disorders (0.68%), which included constipation. There were no new ADRs warranting attention beyond those already described in teneligliptin's package insert. ADRs and serious ADRs in renal function subgroups occurred in 3.24-7.14% and 0.65-5.36% in G1-G5, and 4.49% and 1.92% in patients on dialysis, respectively. Reduction in HbA1c was sustained for 3 years after starting teneligliptin (- 0.70% ± 1.36%, p < 0.001 at 3 years). The least-squares mean changes in HbA1c adjusted for baseline were - 0.76% to - 0.66% in G1-G5 at 3 years. Glycated albumin levels decreased in patients on dialysis (- 2.92% ± 4.78% at 3 years). CONCLUSION: There were no new safety or efficacy concerns about teneligliptin used in long-term, real-world, clinical settings in patients with T2DM with any stages of renal impairment. TRIAL REGISTRATION: Japan Pharmaceutical Information Center clinical trials database identifier: Japic CTI-153047. Plain language summary available for this article.

Dipeptidyl peptidase IV inhibitor-associated bullous pemphigoid: a recently recognized autoimmune blistering disease with unique clinical, immunological and genetic characteristics.

Bullous pemphigoid (BP) is an organ-specific autoantibody-mediated autoimmune blistering skin disorder that tends to affect the elderly. Tense blister formation associated with itchy urticarial erythema is clinically observed in BP, and subepidermal blister formation with eosinophilic infiltration is a histopathological characteristic. BP autoantibodies target two hemidesmosomal components in basal keratinocytes: BP180 and BP230. Anti-BP180 autoantibodies play major roles in blister formation. Although the autoantibody-mediated pathomechanism of blister formation has been extensively studied, little is known about how and why immune tolerance to BP180 may be broken in certain elderly individuals. Recently, BP has been increasingly reported in diabetes mellites (DM) patients receiving dipeptidyl peptidase-IV inhibitors (DPP4is), which are widely used anti-DM drugs. Pharmacovigilance and cohort studies have revealed that DPP4is, especially vildagliptin, teneligliptin, and linagliptin, are a potential risk factor for BP onset. Interestingly, it has been revealed that Japanese DPP4i-BP tends to show a non-inflammatory phenotype, with less erythema than normal BP, and that DPP4i-BP autoantibodies target distinct epitopes on BP180. In addition, human leukocyte antigen-DQB1*03:01 was identified as the major haplotype in Japanese DPP4i-BP. This review summarizes the latest understanding of the pathogenesis of BP, with a special focus on the recently recognized DPP4i-BP.

The Unique Pharmacological and Pharmacokinetic Profile of Teneligliptin: Implications for Clinical Practice.

Teneligliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor that was approved for the treatment of type 2 diabetes mellitus (T2DM) in Japan and Korea and is being researched in several countries. Teneligliptin is a potent, selective, and long-lasting DPP-4 inhibitor with a t½ of approximately 24 h and unique pharmacokinetic properties: it is metabolized by cytochrome P450 (CYP) 3A4 and flavin-containing monooxygenase 3 (FMO3), or excreted from the kidney in an unchanged form. Because of its multiple elimination pathways, dose adjustment is not needed in patients with hepatic or renal impairment, and it is considered to have a low potential for drug-drug interactions. Clinical studies and postmarketing surveillance show that teneligliptin, administered as monotherapy and/or in combination with antihyperglycemic agents, is effective and well tolerated in T2DM patients, including in elderly patients and those with renal impairment. Furthermore, teneligliptin has antioxidative properties, which induce the antioxidant cascade, as well as ·OH scavenging properties. In addition, it has shown endothelial protective effects in several non-clinical and clinical studies. From its unique profile and clinical data, teneligliptin represents a potential therapeutic option in a wide variety of patients, including elderly diabetic patients and those with renal impairment. The fixed-dose combination (FDC) tablet of teneligliptin and canagliflozin has been approved in Japan; this is the first FDC tablet of a DPP-4 inhibitor and sodium glucose co-transporter 2 inhibitor in Japan, and the third globally. The FDC tablet may also provide additional prescribing and adherence benefits.

Effects of Teneligliptin on the Progressive Left Ventricular Diastolic Dysfunction in Patients with Type 2 Diabetes Mellitus in Open-Label, Marker-Stratified Randomized, Parallel-Group Comparison, Standard Treatment-Controlled Multicenter Trial (TOPLEVEL Study): Rationale and Study Design.

BACKGROUND AND AIMS: Diabetes mellitus (DM) can cause left ventricular (LV) diastolic dysfunction, leading to heart failure with preserved ejection fraction (HFpEF). Dipeptidyl peptidase IV (DPP-IV) inhibitors have failed to reduce hospitalization due to HF in type 2 DM (T2D) patients in a large-scale clinical trial, despite their cardiovascular protective effects. Therefore, it is important to investigate whether DPP-IV inhibitors can improve LV diastolic dysfunction in T2D patients. The aim of the study was to evaluate whether teneligliptin, the strongest of the DPP-IV inhibitors, improves LV dysfunction or prevents the worsening of LV diastolic function in T2D patients. METHODS: The TOPLEVEL study is designed as an open-labeled, marker-stratified randomized, parallel-group comparison, standard treatment-controlled multicenter study. TOPLEVEL includes two marker-defined subgroups to give treatment recommendations for T2D patients with normal (E/e' < 8) or impaired LV diastolic function (E/e' ≥ 8), where E/e' is the ratio of peak velocity of early transmitral diastolic filling by echocardiography to early diastolic mitral annular velocity by tissue Doppler echocardiography as LV diastolic function. Patients are randomly assigned to either teneligliptin (20 or 40 mg) or the standard treatment group. All patients are followed up for 2 years. The primary endpoint measure is the change in E/e' from baseline and 2 years after enrollment. CONCLUSION AND PERSPECTIVES: TOPLEVEL is a clinical trial of teneligliptin targeting LV diastolic dysfunction in T2D patients. This study demonstrates the effectiveness of DPP-IV inhibitors on LV diastolic dysfunction, an important surrogate endpoint to predict the cardiovascular outcomes of HFpEF (UMIN000014589).

Coadministration of the prostaglandin F2α receptor antagonist preterm labour drug candidate OBE022 with magnesium sulfate, atosiban, nifedipine and betamethasone.

AIMS: To investigate presence or absence of clinically relevant drug interactions (pharmacokinetic and safety/tolerability) of OBE022 with standard-of-care medicines for preterm labour, enabling coadministration and further clinical development. METHODS: Part A: open-label, randomized, 3-period crossover assessing coadministration of single doses of OBE022 (1100 mg) and MgSO4 . Part B: open-label, single-sequence crossover assessing the interactions following administration of OBE022 (1000 mg/day) at steady state coadministered with single doses of atosiban, nifedipine and betamethasone. Twenty-five healthy nonpregnant women of reproductive age were enrolled (Part A: n = 12; Part B: n = 13). RESULTS: OBE022, alone or in combination with standard-of-care medications, was well tolerated. Headache and dizziness were the most frequently reported adverse events; dizziness occurred more often with the nifedipine/OBE022 combination. There were no clinically significant pharmacokinetic interactions when coadministered with MgSO4 . Co-administration had no notable effect on atosiban exposure. Atosiban reduced exposure to OBE002 (peak concentration [Cmax ] 22%, area under the concentration-time curve [AUC] 19%). Coadministration with betamethasone slightly increased betamethasone exposure (Cmax  + 18%, AUC +27%) and OBE002 exposure (Cmax  + 35%, AUC +15%). These changes were not considered clinically significant. Coadministration with nifedipine slightly increased OBE002 exposure (Cmax  + 29%, AUC +24%) and markedly increased nifedipine exposure (Cmax by 2-fold and AUC by 2-fold), which may be clinically significant. CONCLUSIONS: The use of OBE022, a PGF2α antagonist prodrug, in combination with standard-of-care medicines may provide new treatment alternatives for preterm labour. All tested combinations were well tolerated. Nifedipine doses could potentially be reduced or staggered when coadministered with OBE022.

Design, synthesis, modeling studies and biological evaluation of thiazolidine derivatives containing pyrazole core as potential anti-diabetic PPAR-γ agonists and anti-inflammatory COX-2 selective inhibitors.

Nowadays, diabetes and its associated inflammatory complications are important public health problems worldwide. Market limitations of drugs with dual actions as anti-inflammatory (AI) and anti-diabetic have been led to a temptation for focusing on the discovery and development of new compounds with potential AI and anti-diabetic activities. Herein, we synthesized two new series containing pyrazole ring with vicinal diaryl rings as selective COX-2 moiety and thiazolidindione (series 12a-f) or thiazolidinone (series 13a-f) as anti-diabetic moiety and the two moieties were linked together with methylene or methylenehydrazone functionality. The two series were evaluated for their COX inhibition, AI activity and ulcerogenic liability and for the anti-diabetic activity; 12a-f and 13a-f were assessed in vitro against α-glucosidase, ß- glucosidase, in vivo hypoglycemic activity (one day and 15 days studies) in addition to PPARγ activation study. Four compounds (12c, 12f, 13b and 13f) had higher COX-2 S.I. (8.69-9.26) than the COX-2 selective drug celecoxib (COX-2 S.I. = 8.60) and showed the highest AI activities and the lowest ulcerogenicity than other derivatives. Also, two thiazolidindione derivatives 12e and 12f and two thiazolidinone derivatives 13b and 13c showed higher inhibitory activities against α- and ß-glucosidase (% inhibitory activity = 62.15, 55.30, 65.37, 59.08 for α-glucosidase and 57.42, 60.07, 58.19, 66.90 for ß-glucosidase respectively) than reference compounds (acarbose with % inhibitory activity = 49.50 for α-glucosidase and d-saccharic acid 1,4-lactone monohydrate with % inhibitory activity = 53.42 for ß-glucosidase) and also showed good PPAR-γ activation and good hypoglycemic effect in comparison to pioglitazone and rosiglitazone. Moreover, Shape comparison and docking studies were carried out to understand their interaction and similarity with standard drugs.

Phase I studies of AZD1208, a proviral integration Moloney virus kinase inhibitor in solid and haematological cancers.

BACKGROUND: Proviral integration Moloney virus (PIM) kinases (PIM1, 2 and 3) are overexpressed in several tumour types and contribute to oncogenesis. AZD1208 is a potent ATP-competitive PIM kinase inhibitor investigated in patients with recurrent or refractory acute myeloid leukaemia (AML) or advanced solid tumours. METHODS: Two dose-escalation studies were performed to evaluate the safety and tolerability, and to define the maximum tolerated dose (MTD), of AZD1208 in AML and solid tumours. Secondary objectives were to evaluate the pharmacokinetics, pharmacodynamics (PD) and preliminary efficacy of AZD1208. RESULTS: Sixty-seven patients received treatment: 32 in the AML study over a 120-900 mg dose range, and 25 in the solid tumour study over a 120-800 mg dose range. Nearly all patients (98.5%) in both studies experienced adverse events, mostly gastrointestinal (92.5%). Dose-limiting toxicities included rash, fatigue and vomiting. AZD1208 was not tolerated at 900 mg, and the protocol-defined MTD was not confirmed. AZD1208 increased CYP3A4 activity after multiple dosing, resulting in increased drug clearance. There were no clinical responses; PD analysis showed biological activity of AZD1208. CONCLUSIONS: Despite the lack of single-agent clinical efficacy with AZD1208, PIM kinase inhibition may hold potential as an anticancer treatment, perhaps in combination with other agents.

OBE022, an Oral and Selective Prostaglandin F2α Receptor Antagonist as an Effective and Safe Modality for the Treatment of Preterm Labor.

Preterm birth is the major challenge in obstetrics, affecting ∼10% of pregnancies. Pan-prostaglandin synthesis inhibitors [nonsteroidal anti-inflammatory drugs (NSAIDs)] prevent preterm labor and prolong pregnancy but raise concerns about fetal renal and cardiovascular safety. We conducted preclinical studies examining the tocolytic effect and fetal safety of the oral prodrug candidate OBE022 [(S)-2-amino-3-methyl-butyric acid (S)-3-{[(S)-3-(biphenyl-4-sulfonyl)-thiazolidine-2-carbonyl]-amino}-3-(4-fluoro-phenyl)-propyl ester] and its parent OBE002 [(S)-3-(biphenyl-4-sulfonyl)-thiazolidine-2-carboxylic acid [(S)-1-(4-fluoro-phenyl)-3-hydroxy-propyl]-amide], both potent and highly selective antagonist of the contractile prostaglandin F2α (PGF2α ) receptor (FP). Efficacy of OBE022 and OBE002, alone and in combination with other tocolytics, was assessed in human tissues and pregnant animal models for inhibition of uterine contraction and delay of parturition. Selective safety of OBE022 and/or OBE002, compared with NSAID indomethacin, was assessed on renal function, closure of the ductus arteriosus, and inhibition of platelet aggregation. In in vitro studies, OBE002 inhibited spontaneous, oxytocin- and PGF2α -induced human myometrial contractions alone and was more effective in combination with atosiban or nifedipine. In in vivo studies, OBE022 and OBE002 reduced spontaneous contractions in near-term pregnant rats. In pregnant mice, OBE022 delayed RU486 [(8S,11R,13S,14S,17S)-11-[4-(dimethylamino)phenyl]-17-hydroxy-13-methyl-17-prop-1-ynyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-3-one] -induced parturition and exerted synergistic effects in combination with nifedipine. OBE022 and/or OBE002 did not show the fetal side effects of ductus arteriosus constriction, impairment of kidney function, or inhibition of platelet aggregation observed with indomethacin. Orally active OBE022 and OBE002 exhibits potent tocolytic effects on human tissues ex vivo and animal models in vivo without causing the adverse fetal side effects seen with indomethacin. Selectively targeting the FP receptor in combination with existing tocolytics may be an effective strategy for preventing or delaying preterm delivery.

Pharmacokinetics, safety and tolerability of OBE022, a selective prostaglandin F2α receptor antagonist tocolytic: A first-in-human trial in healthy postmenopausal women.

AIMS: Preterm birth remains a significant risk for later disability. The selective inhibition of the prostaglandin F2α receptor has significant advantages for a tocolytic. The prodrug OBE022 and its metabolite OBE002 are novel prostaglandin F2α receptor antagonists under development for treating preterm labour. METHODS: We performed a prospective, first in human, Phase I, dose escalation, placebo-controlled, randomized trial at a clinical trial site in the UK. Placebo, single ascending doses of 10, 30, 100, 300, 1000 or 1300 mg, and multiple ascending doses over 7 days of 100, 300 or 1000 mg day-1 ; were administered to postmenopausal female volunteers. Food interaction was additionally evaluated. RESULTS: Subjects tolerated OBE022 well at all single and multiple doses. No clinically relevant changes in safety parameters were shown and there were no serious adverse events. Observations showed that prodrug OBE022 was readily absorbed and rapidly converted into its equally active stable metabolite OBE002. The plasma level of OBE002 rose with increasing doses, reaching exposure levels that were anticipated to be clinically relevant within 1 h following administration. There was no clinically significant food interaction, with peak exposures reduced to 80% and area under the curve staying bioequivalent. The mean half-life of OBE002 ranged between 8 and 11 h following administration of a single dose and 22-29 h after multiple doses. CONCLUSIONS: Administration of OBE022 was safe and had favourable pharmacokinetic characteristics and no clinically relevant interaction with food. Our results allow further investigation of OBE022 in preterm labour patients.