Influence of renin-angiotensin system blockades on vascular access survival in patients on maintenance hemodialysis.

INTRODUCTION: Results on the association between the use of renin-angiotensin system blockades (RASBs) and vascular access-related outcomes are inconsistent. We aimed to compare vascular access-related outcomes according to the use of RASBs in hemodialysis patients. METHODS: This study used data from a national hemodialysis quality assessment program of the Republic of Korea (n = 54,903). Group 1 was not prescribed any blood pressure-lowering drugs (n = 28,521). Group 2 was prescribed other blood pressure-lowering agents except for RASBs (n = 9571). Group 3 was prescribed RASBs (n = 16,811). Vascular access-related outcomes were classified into intervention-free survival (IFS), thrombosis-free survival (TFS), and vascular access survival (VAS). RESULTS: No significant difference in the three access survival rates was identified among the three groups. The multivariate Cox regression analyses indicated that Group 3 had better outcomes in IFS and TFS than Group 1. The numbers of angioplasties performed were significantly greater in Group 1 than in the other two groups. The numbers of thrombectomies performed were significantly the lowest in Group 3 among all the groups. CONCLUSIONS: Our study revealed different results according to types of access survival in univariate or multivariate analyses. The association of RASBs with favorable outcomes in vascular access remains unclear.

Effect of angiotensin-converting enzyme inhibitors versus that of angiotensin receptor blockers on survival in patients undergoing hemodialysis: a nationwide observational cohort study.

BACKGROUND: This study aimed to evaluate the patient survival rates based on the use of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) in a large cohort of patients undergoing maintenance hemodialysis (HD). METHODS: Data from a national HD quality assessment program were used in this retrospective study. The patients were classified into four groups based on the use of renin-angiotensin system blockers (RASBs) as follows: No group, patients without a prescription of any anti-hypertensive drugs including RASBs; Other group, patients with a prescription of anti-hypertensive drugs excluding RASBs; ACEI group, patients with a prescription of an ACEI; and ARB group, patients with a prescription of an ARB. RESULTS: The 5-year survival rates in the no, other, ACEI, and ARB groups were 68.6%, 67.8%, 70.6%, and 69.2%, respectively. The ACEI group had the best patient survival trend among the four groups. In multivariable Cox regression analyses, no differences were observed between the ACEI and ARB groups. Among young patients and patients without diabetes or heart disease, the ACEI group had the best patient survival among the four groups. However, among patients with DM or heart disease, the ARB group had the best patient survival. CONCLUSIONS: Our study found that patients receiving ACEI and ARB had comparable survival. However, patients receiving ARB had better survival in the subgroups of patients with DM or heart disease, and patients receiving ACEI had better survival in the subgroup of young patients or patients without diabetes or heart disease.

Comparison between the Effects of Allopurinol and Febuxostat on the Survival of Patients on Maintenance Hemodialysis.

INTRODUCTION: There were insufficient pieces of evidence regarding the effect of the two drugs (allopurinol and febuxostat) on patient survival in hemodialysis (HD) patients. Herein, we aimed to compare the efficacy of uric acid-lowering drugs (ULDs) or the type of the drug on patient survival using a representative sample of maintenance HD patients in South Korea. METHODS: This study used data from a national HD quality assessment program and the claims data. Use of ULDs was defined as more than one prescription during the 6 months of each HD quality assessment period. The patients were divided into three groups. Patients who were not prescribed allopurinol or febuxostat were included in group 1 (n = 43,251); patients who were prescribed allopurinol were included in group 2 (n = 9,987); and patients who were prescribed febuxostat were included in group 3 (n = 2,890). RESULTS: Kaplan-Meier curves showed that the survival rate was greatest in group 3 and worst in group 1 among the three groups. Multivariable analysis showed that group 2 had better patient survival compared to group 1; however, there was no significant difference in patient survival between groups 2 and 3. In addition, patients with hyperuricemia or gout had better patient survival compared to those without these diseases. CONCLUSIONS: Our study showed that survival in patients receiving ULDs was not inferior to that of those not receiving ULDs. Patient survival between patients on HD receiving allopurinol and those receiving febuxostat was similar.

Effects of Administration and Intensity of Statins on Mortality in Patients Undergoing Hemodialysis.

(1) Background: Few studies have investigated the association between the intensity of statins and patient survival rates in patients undergoing hemodialysis (HD) as primary outcomes. This study aimed to evaluate patient survival rates according to the intensity of statins using a large sample of patients undergoing maintenance HD. (2) Methods: Data from a national HD quality assessment program were used in this study (n = 53,345). We divided the patients into four groups based on the administration and intensity of statins: Group 1, patients without a prescription of statins (n = 37,944); Group 2, patients with a prescription of a low intensity of statins (n = 700); Group 3, patients with a prescription of a moderate intensity of statins (n = 14,160); Group 4, patients with a prescription of a high intensity of statins (n = 541). (3) Results: Significant differences in baseline characteristics were observed among the four groups. Group 1 had the best patient survival among the four groups in the univariate Cox regression analyses. However, multivariable Cox regression analyses showed that the patient survival rate was higher for Group 3 than for Group 1. Cox regression analyses using data of a balanced cohort showed that, on univariate analyses, the HRs were 0.93 (95% CI, 0.91-0.95, p < 0.001) in Group 2 and 0.95 (95% CI, 0.93-0.96, p < 0.001) in Group 3 compared to that in Group 1. Group 4 had a higher mortality rate than Groups 2 or 3. The results from the cohort after balancing showed a similar trend to those from the multivariable Cox regression analyses. Young age and less comorbidities in Group 1 were mainly associated with favorable survival in Group 1 in the univariate analysis using cohort before balancing. Among the subgroup analyses based on sex, age, presence of diabetes mellitus, and heart disease, most multivariable analyses showed significantly higher patient survival rates in Group 3 than for Group 1. (4) Conclusions: Our study exhibited significant differences in baseline characteristics between the groups, leading to limitations in establishing a robust association between statin intensity and clinical outcomes. However, we conducted various statistical analyses to mitigate these differences. Some results, including multivariable analyses controlling for baseline characteristics and analyses of a balanced cohort using propensity score weighting, indicated improved patient survival in the moderate-intensity statin group compared to non-users. These findings suggest that moderate statin use may be associated with favorable patient survival.

Effect of spironolactone on survival in patients undergoing maintenance hemodialysis.

BACKGROUND: Previous studies have reported inconsistent results regarding the advantages or disadvantages of spironolactone use in patients undergoing hemodialysis (HD). This study aimed to evaluate survival according to the use of spironolactone in a large sample of patients undergoing maintenance HD. METHODS: This retrospective study used laboratory and clinical data from the national HD Quality Assessment Program and claims data. The participants of the quality assessment program were patients who had been undergoing maintenance HD for ≥ 3 months, patients undergoing HD at least twice a week. Patients with no spironolactone prescription during the assessment periods were designated as the control group. Patients with one or more prescriptions of spironolactone during the assessment periods were assigned to the SPR group. RESULTS: The number of patients in the control and SPR groups were 54,588 and 315, respectively. The 5-year survival rates were 69.1% and 59.1% in the control and SPR groups, respectively (P < 0.001). Cox regression analyses showed that the hazard ratio in the SPR group was 1.34 (P < 0.001) in univariate analysis and 1.13 (P = 0.249) in multivariable analysis. Univariate Cox-regression analysis showed a better patient survival rate in the control group than in the SPR group; however, multivariable analyses showed similar patient survival rates between the two groups. CONCLUSION: This study showed no difference in survival between patients undergoing HD with and without spironolactone use.

Clinical Impact of the Use of Warfarin in Patients with Atrial Fibrillation Undergoing Maintenance Hemodialysis.

Background: We evaluated the impact of warfarin use on the clinical outcomes of patients with atrial fibrillation who were undergoing hemodialysis (HD). Methods: A retrospective analysis was conducted utilizing data from patients undergoing maintenance HD who participated in HD quality assessment programs. Patients who were assigned the diagnostic code for atrial fibrillation (n = 4829) were included and divided into two groups based on the use of warfarin: No group (no warfarin prescriptions (n = 4009)), and Warfarin group (warfarin prescriptions (n = 820)). Results: Cox regression analyses revealed that the hazard ratio for all-cause mortality in the Warfarin group was 1.15 (p = 0.005) in univariate analysis and 1.11 (p = 0.047) in multivariable analysis compared to that of the No group. Hemorrhagic stroke was significantly associated with warfarin use, but no significant association between the use of warfarin and ischemic stroke or cardiovascular events was observed. The subgroup results demonstrated similar trends. Conclusions: Warfarin use is associated with a higher risk of all-cause mortality and hemorrhagic stroke, and has a neutral effect on ischemic stroke and cardiovascular events in patients with atrial fibrillation who are undergoing HD, compared to those who are not using warfarin.

Changes in pre-haemodialysis serum creatinine levels over 2 years and long-term survival in maintenance haemodialysis.

BACKGROUND: Pre-haemodialysis (HD) serum creatinine levels are reliable and inexpensive markers of muscle mass and important predictors of survival in patients with stable chronic HD. We aimed to assess whether changes in pre-HD serum creatinine levels during a 2-year period are linked to long-term patient survival. METHODS: We retrospectively analysed patients enrolled in a periodic HD quality assessment program. Of the 21 846 participants in the fourth HD quality assessment program, 13 765 were presented in the fifth, of which 10 299 eligible patients were included in this study. We assessed the change in serum creatinine levels over 2 years. The patients were categorized into the following three groups: stable group (patients with change in serum creatinine < 1 mg/dL during 2 years of HD, n = 5664), increasing group (patients with increase in serum creatinine ≥ 1 mg/dL, n = 2419) and decreasing group (patients with decrease in serum creatinine ≥ 1 mg/dL, n = 2216). RESULTS: The duration of HD at baseline was 62-83 months, with diabetic kidney disease being the most common cause of kidney failure in 36.4% of patients. The 5-year patient survival rates in the stable, increasing and decreasing groups were 69.1%, 71.3% and 66.8%, respectively. The decreasing group had poorer patient survival than the other two groups (P = 0.083 for stable vs. increasing group; P = 0.011 for stable vs. decreasing group; P < 0.001 for increasing vs. decreasing group). There was no significant difference in the cardiovascular event-free survival rate among the three groups. Multivariable Cox regression analyses revealed the highest hazard ratio (HR) for mortality in the decreasing group (HR 1.33, 95% confidence interval [CI] 1.21-1.45, P < 0.001 vs. stable group; HR 1.50, 95% CI 1.34-1.69, P < 0.001 vs. increasing group). The increasing group exhibited a lower risk of mortality than the stable group (HR 0.88, 95% CI 0.81-0.97, P = 0.008). Subgroup analyses based on age, HD vintage, sex, Charlson comorbidity index score, presence of diabetes and baseline serum creatinine level tertiles revealed that the decreasing group exhibited the highest mortality among all subgroups. CONCLUSIONS: Our results demonstrate that changes in pre-HD serum creatinine levels over 2 years of HD were associated with all-cause mortality in patients undergoing HD. This finding suggests a simple and promising approach for clinicians in the prognosis and management of patients undergoing HD.

Effects of Kt/Vurea on outcomes according to age in patients on maintenance hemodialysis.

Background: The guidelines recommended target and minimum single-pool Kt/Vurea are 1.4 and 1.2, respectively, in hemodialysis patients. However, the optimal hemodialysis dose remains controversial. We investigated the effects of Kt/Vurea on patient outcomes according to age, with a focus on older patients. Methods: This study used the hemodialysis quality assessment program and claims datasets. Patients were divided into four subgroups according to age (<65, 65-74, 75-84, and ≥85 years). Each group was divided into three subgroups according to Kt/Vurea : reference (ref) (1.2 ≤ Kt/Vurea ≤ 1.4), low (< 1.2), and high (> 1.4). Results: The low, ref, and high Kt/Vurea groups included 1668, 8156, and 16 546 (< 65 years); 474, 3058, and 7646 (65-74 years); 225, 1362, and 4194 (75-84 years); and 14, 126, and 455 (≥85 years) patients, respectively. The low Kt/Vurea group had higher mortality rates than the ref Kt/Vurea group irrespective of age [adjusted hazard ratio (aHR), 95% confidence interval (CI): 1.23, 1.11-1.36; 1.14, 1.00-1.30; 1.28, 1.09-1.52; and 2.10, 1.16-3.98, in patients aged <65, 65-74, 75-84, and ≥85 years, respectively]. The high Kt/Vurea group had lower mortality rates than the ref Kt/Vurea group in patients aged <65 and 65-74 years (aHR, 95% Cl: 0.87, 0.82-0.92 and 0.93, 0.87-0.99 in patients aged <65 and 65-74 years, respectively). Conclusions: These results support the current recommendations of a minimum Kt/Vurea of 1.2 even in patients age ≥85 years. In young patients, Kt/Vurea above the recommended threshold can be beneficial for survival.

Comparison of Patient Survival According to Erythropoiesis-Stimulating Agent Type of Treatment in Maintenance Hemodialysis Patients.

This study aimed to evaluate the difference in patient survival according to the type of erythropoiesis-stimulating agent (ESA) treatment used in the Korean hemodialysis (HD) population. This retrospective study analyzed the laboratory data from a national HD quality assessment program and the claims of Korea. Included participants were divided into three groups according to the type of ESA used during the 6 months of each assessment period as follows: the EP group (n = 38,043, epoetin-α or epoetin-ß), the DP group (n = 10,054, darbepoetin-α), and the MR group (2253, continuous erythropoietin receptor activator). The ESA doses in the EP, DP, and MR groups were 6451 ± 3586, 5959 ± 3857, and 3877 ± 2275 unit/week, respectively. The erythropoiesis resistance indexes (ERIs) in the three groups were 10.7 ± 6.7, 9.9 ± 7.6, and 6.3 ± 4.1 IU/kg/g/dL, respectively. Kaplan−Meier curves revealed similar rates of patient survival among the three groups (p = 0.530). A multivariate Cox regression analysis showed that the hazard ratios in the DP group and MR group were 1.00 (p = 0.853) and 0.87 (p < 0.001), respectively, compared to that of the EP group. The hazard ratio in the MR group was 0.87 (p = 0.001) compared to that of the DP group. Our study shows that the MR group had comparable or better patient survival than the EP and DP groups in the multivariate analysis. However, the ESA doses and ERI were considerably different among the three groups. It was difficult to determine whether the better patient survival in the MR group originated from the ESA type, ESA dose, ERI, or other hidden factors.

Effects of Proton Pump Inhibitors on Patient Survival in Patients Undergoing Maintenance Hemodialysis.

Data to draw definite conclusions regarding the association between proton pump inhibitor (PPI) and all-cause mortality in patients undergoing hemodialysis (HD) remain insufficient. The object of this retrospective study was to assess the impact of PPIs on patient survival within a substantial cohort of individuals receiving maintenance HD. To achieve this, the study employed laboratory and clinical data sourced from the 4th, 5th, and 6th National HD Quality Assessment Programs. The programs included patients undergoing maintenance HD (n = 54,903). Based on the PPI prescription data collected over the 6-month HD quality assessment, the patients were categorized into three groups: Group 1, comprising individuals with not prescription; Group 2, consisting of patients prescribed PPIs for less than 90 days; and Group 3, comprising patients prescribed PPIs for 90 days or more. The respective number of patients in Groups 1, 2, and 3 was 43,059 (78.4%), 5065 (9.2%), and 6779 (12.3%), respectively. Among the study groups, the 5-year survival rates were as follows: Group 1-70.0%, Group 2-68.4%, and Group 3-63.0%. The hazard ratio for Group 3 was 1.09 (95% CI, 1.04 to 1.15; p < 0.001) and 1.10 (95% CI, 1.03 to 1.18; p = 0.007) compared to Groups 1 or 2 based on multivariable analysis. Multivariable analyses revealed a lower rate of patient survival in Group 3 compared to the other groups, while Groups 1 and 2 exhibited similar patient survival rates. Our study revealed a significant association between long-term PPI usage and increased mortality among patients undergoing HD. However, distinct trends were observed in subgroup analyses. The association between long-term PPI usage and mortality was prominent in patients who did not have a high gastrointestinal burden or comorbidities. Meanwhile, this association was not observed in patients who did have a high gastrointestinal burden or comorbidities.

Association of Renin-Angiotensin System Blockers with Survival in Patients on Maintenance Hemodialysis.

Additional studies are needed to confirm whether the use of renin-angiotensin system blockers (RASBs) induces survival benefits in patients on hemodialysis (HD). This study aimed to evaluate patient survival with the use of RASBs in a large sample of maintenance HD patients. This study used data from the national HD quality assessment program and claim data from South Korea (n = 54,903). A patient using RASBs was defined as someone who had received more than one prescription during the 6 months of each HD quality assessment period. The patients were divided into three groups as follows: Group 1, no prescription for anti-hypertensive drugs; Group 2, prescription for anti-hypertensive drugs other than RASBs; and Group 3, prescription for RASBs. The five-year survival rates in Groups 1, 2, and 3 were 72.1%, 64.5%, and 66.6%, respectively (p < 0.001 for Group 1 vs. Group 2 or 3; p = 0.001 for Group 2 vs. Group 3). Group 1 had the highest patient survival rates among the three groups, and Group 3 had higher patient survival rates compared to Group 2. Group 3 had higher patient survival rates than Group 2; however, the difference in patient survival rates between Group 2 and Group 3 was relatively small. Multivariate Cox regression analyses showed similar trends as those of univariate analyses. The highest survival rates from our study were those of patients who had not used anti-hypertensive drugs. Between patients treated with RASBs and those with other anti-hypertensive drugs, patient survival rates were higher in patients treated with RASBs.

Correlation between Statin Solubility and Mortality in Patients on Chronic Hemodialysis.

This study aimed to evaluate the effect of statin solubility on the survival of patients undergoing hemodialysis (HD). This retrospective study used laboratory and clinical data from a national HD quality assessment program and claims data (n = 53,345). The use of statins was defined as prescription ≥30 days during 6 months of each HD quality assessment period. We divided the patients into three groups based on the use and solubility of statins: No group, patients without a prescription of statins (n = 37,944); Hydro group, patients with a prescription of hydrophilic statins (n = 2823); and Lipo group, patients with a prescription of lipophilic statins (n = 12,578). The 5-year survival rates in the No, Hydro, and Lipo groups were 69.6%, 67.9%, and 67.9%, respectively (p < 0.001 for the trend). Multivariable Cox regression analyses showed that the Lipo group had better patient survival than the No group. However, multivariable analyses did not show statistical significance between the Hydro and No or Lipo groups. In all subgroups based on sex, age, presence of diabetes mellitus, and heart disease, the Lipo group had better patient survival than the No group. We identified no significant association between hydrophilic and lipophilic statins and patient survival. However, patients taking lipophilic statins had a modest survival benefit compared with those who did not receive statins.

Association between Iron Status and Survival in Patients on Chronic Hemodialysis.

The aim of this study was to evaluate survival rates according to iron status in patients undergoing maintenance hemodialysis (HD). Thus, the National HD Quality Assessment Program dataset and claims data were used for analysis (n = 42,390). The patients were divided into four groups according to their transferrin saturation rate and serum ferritin levels: Group 1 (n = 34,539, normal iron status); Group 2 (n = 4476, absolute iron deficiency); Group 3 (n = 1719, functional iron deficiency); Group 4 (n = 1656, high iron status). Using univariate and multivariable analyses, Group 1 outperformed the three other groups in terms of patient survival. Using univariate analysis, although Group 2 showed a favorable trend in patient survival rates compared with Groups 3 and 4, the statistical significance was weak. Group 3 exhibited similar patient survival rates to Group 4. Using multivariable Cox regression analysis, Group 2 had similar patient survival rates to Group 3. Subgroup analyses according to sex, diabetic status, hemoglobin level ≥ 10 g/dL, and serum albumin levels ≥ 3.5 g/dL indicated similar trends to those of the total cohort. However, subgroup analysis based on patients with a hemoglobin level < 10 g/dL or serum albumin levels < 3.5 g/dL showed a weak statistical significant difference compared with those with hemoglobin level ≥ 10 g/dL, or serum albumin levels ≥ 3.5 g/dL. In addition, the survival difference between Group 4 and other groups was greater in old patients than in young ones. Patients with a normal iron status had the highest survival rates. Patient survival rates were similar or differed only modestly among the groups with abnormal iron status. In addition, most subgroup analyses revealed similar trends to those according to the total cohort. However, subgroup analyses based on age, hemoglobin, or serum albumin levels showed different trends.

Influence of Different Types of ß-Blockers on Mortality in Patients on Hemodialysis.

Previous results regarding the association between types of ß-blockers and outcomes in patients on hemodialysis (HD) were inconsistent. Our study aimed to evaluate patient survival according to the type of ß-blockers administered using a large sample of patients with maintenance HD. Our study included patients on maintenance HD patients from a national HD quality assessment program (n = 54,132). We divided included patients into four groups based on their use and type; Group 1 included patients without a prescription of ß-blockers, Group 2 included patients with a prescription of dialyzable and cardioselective ß-blockers, Group 3 included patients with a prescription of non-dialyzable and non-cardioselective ß-blockers, and Group 4 included patients with prescription of non-dialyzable and cardioselective ß-blockers. The number of patients in Groups 1, 2, 3, and 4 were 34,514, 2789, 15,808, and 1021, respectively. The 5-year survival rates in Groups 1, 2, 3, and 4 were 69.3%, 66.0%, 68.8%, and 69.2%, respectively. Univariate Cox regression analyses showed the hazard ratios to be 1.10 (95% CI, 1.04-1.17) in Group 2 and 1.05 (95% CI, 1.02-1.09) in Group 3 compared to Group 1. However, multivariate Cox regression analyses did not show statistical significance among the four groups. Our study showed that there was no significant difference in patient survival based on the use or types of ß-blockers.

Dialysis specialist care and patient survival in hemodialysis facilities: a Korean nationwide cohort study.

BACKGROUND: It is important for the dialysis specialist to provide essential and safe care to hemodialysis (HD) patients. However, little is known about the actual effect of dialysis specialist care on the survival of HD patients. We therefore investigated the influence of dialysis specialist care on patient mortality in a nationwide Korean dialysis cohort. METHODS: We used an HD quality assessment and National Health Insurance Service claims data from October to December 2015. A total of 34,408 patients were divided into two groups according to the proportion of dialysis specialists in their HD unit, as follows: 0%, no dialysis specialist care group, and ≥50%, dialysis specialist care group. We analyzed the mortality risk of these groups using the Cox proportional hazards model after matching propensity scores. RESULTS: After propensity score matching, 18,344 patients were enrolled. The ratio of patients from the groups with and without dialysis specialist care was 86.7% to 13.3%. The dialysis specialist care group showed a shorter dialysis vintage, higher levels of hemoglobin, higher single-pool Kt/V values, lower levels of phosphorus, and lower systolic and diastolic blood pressures than the no dialysis specialist care group. After adjusting demographic and clinical parameters, the absence of dialysis specialist care was a significant independent risk factor for all-cause mortality (hazard ratio, 1.10; 95% confidence interval, 1.03-1.18; p = 0.004). CONCLUSION: Dialysis specialist care is an important determinant of overall patient survival among HD patients. Appropriate care given by dialysis specialists may improve clinical outcomes of patients undergoing HD.

Novel C-aryl glucoside SGLT2 inhibitors as potential antidiabetic agents: Pyridazinylmethylphenyl glucoside congeners.

Novel C-aryl glucoside SGLT2 inhibitors containing pyridazine motif were designed and synthesized for biological evaluation. Among the compounds tested, pyridazine containing methylthio moiety 22l or thiadiazole ring 22ah showed the best in vitro inhibitory activities in this series (IC(50)=13.4, 11.4nM, respectively) against SGLT2 to date. Subsequently, compound 22l exhibited reasonable urinary glucose excretion and glucosuria in normal SD rats, thereby demonstrating that this pyridazine series possesses both in vitro SGLT2 inhibition and in vivo efficacy, albeit to a lower degree.

Arylpiperazine-containing pyrimidine 4-carboxamide derivatives targeting serotonin 5-HT(2A), 5-HT(2C), and the serotonin transporter as a potential antidepressant.

Pyrimidine usually has good pharmacokinetic properties as a drug substance and considerable efforts have been devoted to develop pyrimidine derivatives into drug candidates. Arylpiperazine-containing pyrimidine 4-carboxamide derivatives were synthesized and evaluated for binding to serotonin receptors and transporter. Pyrimidine derivatives showed good antidepressant activity in FST (forced swimming test) animal model and also displayed no appreciable inhibitory activity against hERG channel blocking assay. Herein SAR studies of pyrimidine derivatives targeting serotonin receptors and transporter will be disclosed.

Arylpiperazine-containing pyrrole 3-carboxamide derivatives targeting serotonin 5-HT(2A), 5-HT(2C), and the serotonin transporter as a potential antidepressant.

Arylpiperzine-containing pyrrole 3-carboxamide derivatives were synthesized and evaluated as novel antidepressant compounds. The various analogues were efficiently prepared and bio-assayed for binding to 5-HT(2A), 5-HT(2C) receptor, and 5-HT transporter. Based on their in vitro and in vivo activities as well as selectivity over other neurotransmitter receptors and PK profiles, 33 and 34 were identified as lead compounds. Consequently, this pyrrole series of compounds appears to be promising enough to warrant further investigation.

Novel C-aryl glucoside SGLT2 inhibitors as potential antidiabetic agents: 1,3,4-Thiadiazolylmethylphenyl glucoside congeners.

Novel C-aryl glucoside SGLT2 inhibitors containing 1,3,4-thiadiazole moieties were designed and synthesized. Among the compounds tested, biaryl-type compounds containing pyrazine 59, 2-furan 61, and 3-thiophene 71 showed the best in vitro inhibitory activities to date (IC(50) = 3.51-7.03 nM) against SGLT2. A selected compound 61, demonstrated reasonable blood glucose-lowering effects, indicating that the information obtained from the SAR studies in this 1,3,4-thiadiazolylmethylphenyl glucoside series might help to design more active SGLT2 inhibitors that are structurally related.

Discovery of 2-(4-((1H-1,2,4-triazol-1-yl)methyl)-5-(4-bromophenyl)-1-(2-chlorophenyl)-1H-pyrazol-3-yl)-5-tert-butyl-1,3,4-thiadiazole (GCC2680) as a potent, selective and orally efficacious cannabinoid-1 receptor antagonist.

Structure-activity relationship studies in a series of diarylpyrazolyl thiadiazoles identified cannabinoid-1 receptor antagonists with excellent potency and selectivity. Based on its exceptional in vivo efficacy in animal models and its favorable pharmacokinetic and toxicological profiles, 2-(4-((1H-1,2,4-triazol-1-yl)methyl)-5-(4-bromophenyl)-1-(2-chlorophenyl)-1H-pyrazol-3-yl)-5-tert-butyl-1,3,4-thiadiazole (GCC2680) was selected as a preclinical candidate for the treatment of obesity.