Endothelin receptor antagonists for the treatment of diabetic nephropathy:A meta-analysis and systematic review

BACKGROUND Diabetic nephropathy(DN)is the main cause of chronic kidney disease and endstage renal disease worldwide.Although available clinical trials have shown that endothelin receptor(ER)antagonists may be a novel and beneficial drug for DN,no consistent conclusions regarding their sufficient effectiveness and safety for patients with DN have been presented.AIM To assess the effectiveness and safety of ER antagonists among patients with DN.METHODS The EMBASE,PubMed,MEDLINE,Cochrane,and ClinicalTrials.gov databases were searched without any language restrictions.Relative risks with 95%confidence intervals(CIs)for dichotomous data and mean differences or standardized mean difference with 95%CIs for continuous data were calculated using Review Manager 5.3 software.Publication bias was assessed using Egger’s test with Stata/SE software.RESULTS We enrolled seven studies with six data sets and 5271 participants.The ER antagonists group showed a significantly greater reduction in albuminuria and more patients with 40%reduction in urinary albumin-to-creatinine ratio than the control group(P<0.0001 and P=0.02,respectively).Subgroup analysis for reductions in estimated glomerular filtration rate(eGFR)showed that for the middle-dosage subgroup,the ER antagonists group exhibited lower eGFR reduction than the control group(P<0.00001;mean difference,0.7095%CI:0.66,0.74).Moreover,significant reductions in systolic and diastolic blood pressure were observed in the invention group.CONCLUSION ER blockades combined with angiotensin converting enzyme inhibitor/angiotensin II type 1 receptor blockers may be an effective treatment to lower blood pressure and reduce proteinuria in DN with declined eGFR.However,attention should be given to adverse events,including cardiac failure,anemia,and hypoglycemia,as well as serious adverse events.

Spectrofluorimetric method for determination of some angiotensin II receptor antagonists

A simple, rapid, accurate and highly sensitive spectrofluorimetric method has been developed for determination of some angiotensin II receptor antagonists (AIIRA’s), namely Losartan potassium (Los-K), Irbesartan (Irb), Valsartan (Val) and Candesartan cilexetil (Cand) in pure forms as well as in their pharmaceutical dosage forms. All the variables affecting the relative fluorescence intensity (RFI) were studied and optimized. Under the optimum conditions, linear relationships with good correlation coefflcients (0.9982–0.9991) were obtained over the concentration range from 0.006 mg/mL to 1.7 mg/mL. Good accuracy and precision were successfully obtained for the analysis of tablets containing each drug alone or combined with hydrochlorothiazide (HCTZ) without interferences from the co-formulated HCTZ or the additives commonly present in tablets.

Design and synthesis of 2-alkylbenzimidazole derivatives as novel non-peptide angiotensin Ⅱ AT1 receptor antagonists

A series of 2-alkylbenzimidazole derivatives 9a-n have been designed and synthesized as a novel class of non-peptide angiotensin H AT1 receptor antagonists. The synthesized compounds were evaluated for their antagonism of angiotensin H, induced contraction in the rabbit thoracic aortic ring and the results showed that compounds 9a, 9g and 9j exhibited potent antagonistic activity of AT1 receptor.

Support vector classification for SAR of 5-HT3 receptor antagonists

In this work, support vector classification （SVC） algorithm was used to build structure-activity relationship （SAR） model of the 5-hydroxytryptamine type 3 （5-HT3 ） receptor antagonists with 26 compounds. In a benchmark test, SVC was compared with several techniques of machine learning currently used in the field. The prediction performance of the model was discussed on the basis of the leave-one-out cross-validation. The results show that the accuracy of prediction of SVC model was higher than those of back propagation artificial neural network （BP ANN）, K-nearest neighbor （KNN） and Fisher methods.

Therapy for acute pancreatitis with platelet-activating factor receptor antagonists

Acute pancreatitis (AP) causes release of platelet- activating factor (PAF), which induces systemic effects that contribute to circulatory disturbances and multiple organ failure. PAF is a cell surface secretion of bioactive lipid, which could produce physiological and pathological effects by binding to its cell surface receptor called platelet-activating factor receptor (PAF-R). Studies showed that PAF participates in the occurrence and development of AP and administration of platelet-activating factor receptor antagonists (PAF-RAs) could significantly reduce local and systemic events after AP. PAF has also been implicated as a key mediator in the progression of severe AP, which can lead to complications and unacceptably high mortality rates. Several classes of PAF-RA show PAF- RAs significant local and systemic effects on reducing inflammatory changes. As a preventive treatment, PAF-RA could block a series of PAF-mediated inflammatory injury and thus improve the prognosis of AP. This review introduces the important role of PAF-RA in the treatment of AP.

Effect of endothelin-1 receptor antagonists on histological and ultrastructural changes in the pancreas and trypsinogen activation in the early course of caerulein-induced acute pancreatitis in rats

AIM: To assess the effect of non-selective ETA/B (LU 302872)and selective ETA (LU 302146) antagonist on pancreatic histology and ultrastructure of acinar cells in connection with trypsinogen activation in early caerulein-induced AP.METHODS: Male Wistar rats with caerulein-induced AP,lasting 4 h, were treated i.p. with 10 and 20 mg/kg b.w.of each antagonist. Edema, inflammatory infiltration,necrosis and vacuolization of acinar cells in the pancreas were scored at 0-3 scale. Free active trypsin (FAT), total potential trypsin (TPT) after activation with enterokinase,and index of trypsinogen activation (%FAT/TPT) were assayed in pancreatic homogenates.RESULTS: In untreated AP, the edema, inflammatory infiltration, necrosis and vacuolization increased as compared to control healthy rats (P＜0.01). None of the treatment exerted any meaningful effect on the edema and inflammatory infiltration. The selective antagonist increased slightly the necrosis score to 0.82±0.06 at higher dose (P＜0.05) vs 0.58±0.06 in untreated AP. The nonselective antagonist increased slightly the vacuolization score to 2.41±0.07 at higher dose (P＜0.01) vs 1.88±0.08in untreated AP. The decrease in the number of zymogen granules, disorganization of endoplasmic reticulum,autophagosomes and cytoplasmic vacuoles were more prominent in treated AP than in untreated AP groups.%FAT/TPT in untreated AP increased about four times (18.4±3.8 vs4.8±1.3 in control group without AP, P＜0.001).Treatment of AP with both antagonists did not affect significantly augmented trypsinogen activation.CONCLUSION: The treatment with endothelin-1 receptors (non-selective ETA/B and selective ETA) antagonists has essential effect neither on the edema and inflammatory infiltration nor on trypsinogen activation observed in the early course of caerulein-induced AP. Nevertheless a slight increase of the necrosis and vacuolization score and some of the ultrastructural data could suggest the possibility of their undesired effects in caerulein-induced AP at investigated doses.

Renin-angiotensin system blockers-SGLT2 inhibitorsmineralocorticoid receptor antagonists in diabetic kidney disease:A tale of the past two decades!

Several pharmacological agents to prevent the progression of diabetic kidney disease(DKD)have been tested in patients with type 2 diabetes mellitus(T2DM)in the past two decades.With the exception of renin-angiotensin system blockers that have shown a significant reduction in the progression of DKD in 2001,no other pharmacological agent tested in the past two decades have shown any clinically meaningful result.Recently,the sodium-glucose cotransporter-2 inhibitor(SGLT-2i),canagliflozin,has shown a significant reduction in the composite of hard renal and cardiovascular(CV)endpoints including progression of end-stage kidney disease in patients with DKD with T2DM at the top of reninangiotensin system blocker use.Another SGLT-2i,dapagliflozin,has also shown a significant reduction in the composite of renal and CV endpoints including death in patients with chronic kidney disease(CKD),regardless of T2DM status.Similar positive findings on renal outcomes were recently reported as a top-line result of the empagliflozin trial in patients with CKD regardless of T2DM.However,the full results of this trial have not yet been published.While the use of older steroidal mineralocorticoid receptor antagonists(MRAs)such as spironolactone in DKD is associated with a significant reduction in albuminuria outcomes,a novel non-steroidal MRA finerenone has additionally shown a significant reduction in the composite of hard renal and CV endpoints in patients with DKD and T2DM,with reasonably acceptable side effects.

Novel Method for Synthesis of Diarylpyrazole Derivatives as Cannabinoid CB_1 Receptor Antagonists

A novel and efficient method was developed for the synthesis of diarylpyrazole derivatives as cannabinoid CB1 receptor antagonist via four step reactions. The key step was the synthesis of a diarylpyrazole skeleton, which involved initial condensation of the sodium salt of compound 12 with diazonium compounds, and further cyclization by heating at reflux in acetic acid. Eight diarylpyrazole derivatives and nine new synthesized compounds were characterized by 1H NMR, IR, MS, and elemental analysis. The reaction conditions were mild and the overall yields of the target compounds ranged from 26% to 44%.

Motor Effects of 1,3-Disubstituted 8-Styrylxanthines as A_(1) and A_(2) Adenosine-Receptor Antagonists in Rats

A series of 1,3-substituted 8-styrylxanthines (11a-d) was synthesized, under chemo- and regioselective conditions, in a good overall yield. The compounds showed affinity towards both A1 and A2A-adenosine receptors by radioligand binding by means of in vitro assays. The (E)-3-ethyl-1-propyl-8-styrylxanthine (11a) showed the greatest affinity towards the A2A receptor, whereas (E)-3-pentyl-1-propyl-8-styrylxanthine (11d) showed the greatest affinity for the A1 receptor. When the 8-styrylxanthines 11a (A15Et) and 11c (A15Bu) were administrated in rats, which were previously injured with 6-hydroxydopamine at the substantia nigra pars compacta (SNc), the turning behavior decreased 50%. Based on these results we propose to A15Et as a potential compound to treat some symptoms of Parkinson’s disease.

Advances in the research and application of neurokinin-1 receptor antagonists

Recently,the substance P(SP)/neurokinin-1 receptor(NK-1R)system has been found to be involved in various human pathophysiological disorders including the symptoms of coronavirus disease 2019(COVID-19).Besides,studies in the oncological field have demonstrated an intricate correlation between the upregulation of NK-1R and the activation of SP/NK-1R system with the progression of multiple carcinoma types and poor clinical prognosis.These findings indicate that the modulation of SP/NK-1R system with NK-1R antagonists can be a potential broad-spectrum antitumor strategy.This review updates the latest potential and applications of NK-1R antagonists in the treatment of human diseases and cancers,as well as the underlying mechanisms.Furthermore,the strategies to improve the bioavailability and efficacy of NK-1R antagonist drugs are summarized,such as solid dispersion systems,nanonization,and nanoencapsulation.As a radiopharmaceutical therapeutic,the NK-1R antagonist aprepitant was originally developed as radioligand receptor to target NK-1R-overexpressing tumors.However,combining NK-1R antagonists with other drugs can produce a synergistic effect,thereby enhancing the therapeutic effect,alleviating the symptoms,and improving patients’quality of life in several diseases and cancers.

Impact of antagonist peptides and chelators on the diagnostic performance of PET/CT using gallium-68-labeled somatostatin receptor antagonists

Objective: Different SSTR2 antagonists have been developed. This study aims to evaluate the impact of different peptides and chelators on the diagnostic performance of SSTR2 antagonists in well-differentiated NETs.Methods: In this prospective study, participants were equally randomized into 2 arms: arm A, participants would undergo a whole-body^(68)Ga-NODAGA-LM3 PET/CT scan on the first day and^(68)Ga-DOTA-LM3 PET/CT scan on the second day;arm B, participants would undergo a whole-body^(68)Ga-NODAGA-LM3 PET/CT scan on the first day and^(68)Ga-NODAGA-JR11 PET/CT scan on the second day. Biodistribution in normal organs, lesion detection ability, and tumor uptakes were compared within each arm.Results: A total of 40 participants (age, 49.5 ± 13.4, 21 men), 20 in each arm, were recruited in the study. In arm A,^(68)Ga-DOTA-LM3 showed lower background. However, the lesion detection ability (overall lesion detected, 445 vs 548;P = .005) and the lesion uptake (overall lesions SUVmax, 19.8 ± 17.2 vs 35.3 ± 28.8;P < .001) was significantly lower than those of^(68)Ga-NODAGA-LM3. In arm B, both^(68)Ga-NODAGA-LM3 and^(68)Ga-NODAGA-JR11 showed similar biodistribution and lesion uptake (SUVmax, 28.5 ± 23.8 vs 25.0 ± 20.0;P < .001) despite minor differences. The lesion detection ability was the same between these 2 tracers (overall lesion detected, 503 vs 503).Conclusions: The diagnostic performance of SSTR2 antagonists was sensitive to chelators. Both^(68)Ga-NODAGA-LM3 and^(68)Ga-NODAGA-JR11 outperformed^(68)Ga-DOTA-LM3 with higher lesion uptake and detection ability, of which^(68)Ga-NODAGA-LM3 had marginally but significantly higher lesion uptake.

C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 pathway as a therapeutic target and regulatory mechanism for spinal cord injury

Spinal cord injury involves non-reversible damage to the central nervous system that is characterized by limited regenerative capacity and secondary inflammatory damage.The expression of the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis exhibits significant differences before and after injury.Recent studies have revealed that the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis is closely associated with secondary inflammatory responses and the recruitment of immune cells following spinal cord injury,suggesting that this axis is a novel target and regulatory control point for treatment.This review comprehensively examines the therapeutic strategies targeting the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis,along with the regenerative and repair mechanisms linking the axis to spinal cord injury.Additionally,we summarize the upstream and downstream inflammatory signaling pathways associated with spinal cord injury and the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis.This review primarily elaborates on therapeutic strategies that target the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis and the latest progress of research on antagonistic drugs,along with the approaches used to exploit new therapeutic targets within the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis and the development of targeted drugs.Nevertheless,there are presently no clinical studies relating to spinal cord injury that are focusing on the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis.This review aims to provide new ideas and therapeutic strategies for the future treatment of spinal cord injury.

Effects of endothelin B receptor antagonists, BQ788 and ET-1_(11-21) fragment on the bronchoconstriction elicited by isocapnic hyperpnea in guinea pigs

Objective To explore the role of endothelin (ET) in the pathogenesis of exercise induced asthma (EIA), we investigated the effects of ET B receptor antagonists, ET 1 11 21 fragment and N cis 2,6 dimethylpi^peridinocardonyl L γ methylleucyl D 1 methoxycarbonyl tryptophanyl D norleucine (BQ788) on broncho^constriction elicited by isocapnic hyperpnea in guinea pigs Methods Eighteen pathogen free Hartley guinea pigs were randomly divided into three groups A: normal saline (NS) inhalation control group (n=6), B: BQ788 group (n=6), and C: ET 1 11 21 fragment group (n=6) Guinea pigs were anesthetized with pentobarbital sodium After measuring the basal value of lung resistance (R L) and dynamic compliance of the respiratory system (Cdyn), NS (0 96?ml), BQ788 (9?nmol) and ET 1 11 21 fragment (9?nmol) were inhaled A rodent respirator with a dry 5%CO 2-95%O 2 mixture at room temperature provided mechanical ventilation (V T 8?ml/animal, 100 breaths/min) for 5?min R L and Cdyn of the 3 groups were measured again after isocapnic hyperpnea challenge Results In the control group, isocapnic hyperpnea of dry gas elicited a marked increase in R L and decrease in Cdyn R L and Cdyn of the guinea pigs from BQ788 group and ET 1 11 21 fragment group did not change significantly Conclusion It was demonstrated that selective ET B receptor antagonists, ET 1 11 21 fragment and BQ788, inhibited the bronchoconstriction induced by isocapnic hyperpnea in guinea pigs The data showed that ETs are potent constrictors of guinea pig airway smooth muscle via a direct effect on ET receptors It was suggested that ET receptor antagonists, especially ET B receptor antagonist, might be beneficial in preventing EIA

A family of novel bifunctional organocatalysts:Highly enantioselective alcoholysis of meso cyclic anhydrides and its application for synthesis of the key intermediate of P2X_7 receptor antagonists

A family of novel squaramides/sulfamides based on 1,2-alkamine was developed as chiral bifunctional catalysts to promote the asymmetric alcoholysis of meso cyclic anhydrides. The hemiesters were obtained in high yield with up to 93% ee. The usefulness of this methodology was demonstrated in the asymmetric synthesis of the key intermediate of P2X7 receptor antagonists.

5-HT_(3) receptor antagonists protect against pressure overload-induced cardiac hypertrophy in murine

Activation of cardiac sympathetic afferent reflex results in the increase of sympathetic activity.Serotonin(5-HT)activates cardiac sympathetic afferent through stimulating 5-HT_(3) receptors,the aim of present study is to test whether 5-HT_(3) receptor antagonists protect against cardiac hypertrophy.Cardiac hypertrophy induced by TAC for 4 weeks in mice was significantly inhibited by administration of 5-HT_(3) receptor antagonists,ondansetron(2.5 mg/kg,ip.)or tropisetron(2.5 mg/kg,ip.).Histological analysis revealed that the increased cardiac fibrosis in hypertrophic heart was relieved by ondansetron or tropisetron treatment.Ondansetron or tropisetron reduced the elevated plasma level of noradrenalin in mice with cardiac hypertrophy.Ondansetron and tropisetron had no effect on cardiomyocte hypertrophy induced by phenylephrine treatment in vitro.Finally,we took tropisetron as the representative drug and examined the effects of tropisetron on the desensitization of cardiac b-adrenergic receptor in rat treated with abdominal aortic banding(AB).Results showed that tropisetron restored the desensitization of cardiac b-adrenergic receptor in AB-treated rats.In conclusion,5-HT_(3) receptor antagonists protected against cardiac hypertrophy and restored the desensitization of cardiac adrenergic responsiveness,the mechanism in which may be through reducing the sympathetic activity.

Design,synthesis and biological evaluation of 1,4-dihydrothieno[3′,2′:5,6]thiopyrano[4,3-c]pyrazole-3-carboxylic amide derivatives as potential estrogen receptor antagonists

The estrogen receptor is a target for therapeutic agents for hormone replacement in menopausal women,osteoporosis, reproductive cancers such as breast cancer,uterine cancer and prostate cancer.1,4-Dihydrothieno[3＇,2＇：5,6]thiopyrano[4,3- c]pyrazole-3-carboxylic amide derivatives were designed,synthesized and biological evaluated as potential estrogen receptor antagonists.

EFFECTS OF ENDOTHELIN-1 RECEPTOR ANTAGONISTS BO123 AND BQ610

Using endothelin-1 (ET-1) antagonists BQ123 and BQ610. we tested whether endogenous ET-1 contributes to ischemia / re-perfusion injury in isolated. Langendorff rat hearts. BQ123 (7μg/min) and BQ610 (1.75μg/ min) did not affect mechanical function or coronary flow and shifted the dose-response curves for ET-1 (boluses of 4-400 pmol) significantly to the right. Isovolumic rat hearts were

Impact of antagonist peptides and chelators on the diagnostic performance of PET/CT using gallium-68 labeled somatostatin receptor antagonists

Objective:Different SSTR2 antagonists have been developed.This study aims to evaluate the impact of different peptides and chelators on the diagnostic performance of SSTR2 antagonists in well-differentiated NETs.Methods:In this prospective study,participants were equally randomized into two arms:Arm A,participants would undergo a whole-body 68Ga-NODAGA-LM3 PET/CT scan on the 1st day and 68Ga-DOTA-LM3 PET/CT scan on the 2nd day;Arm B,participants would undergo a whole-body 68Ga-NODAGA-LM3 PET/CT scan on the 1st day and 68Ga-NODAGA-JR11 PET/CT scan on the 2nd day.Biodistribution in normal organs,lesion detection ability,and tumor uptakes were compared within each Arm.Results:A total of 40 participants(age,49.5±13.4,21 men),20 in each arm,were recruited in the study.In Arm A,68Ga-DOTA-LM3 showed lower background.However,the lesion detection ability(overall lesion detected,445 versus 548,P=0.005)and the lesion uptake(overall lesions SUVmax,19.8±17.2 versus 35.3±28.8,P<0.001)was significantly lower than those of 68Ga-NODAGA-LM3.In Arm B,both 68Ga-NODAGA-LM3 and 68Ga-NODAGA-JR11 showed similar biodistribution and lesion uptake(SUVmax,28.5±23.8 versus 25.0±20.0,P<0.001)despite minor differences.The lesion detection ability was the same between these two tracers(overall lesion detected,503 versus 503).Conclusions:The diagnostic performance of SSTR2 antagonists was sensitive to chelators.Both 68Ga-NODAGA-LM3 and 68Ga-NODAGA-JR11 outperformed 68Ga-DOTA-LM3 with higher lesion uptake and detection ability,of which 68Ga-NODAGA-LM3 had marginally but significantly higher lesion uptake.

Possible Mechanism of Action of Neurokinin-1 Receptors （NK1R） Antagonists

Recently, NK1R （Neurokinin-1 receptors） take attention as new and promising target in anticancer drug development area. It has been proved that non-peptide NK1R antagonists L-733,060, aprepitant and L-732,138 inhibited tumor growth in several cancer cell lines. For the development of novel NK1R antagonists as antitumor agents, heterocyclic compounds which were previously synthesized by our team, tested for their cytotoxic activities in several cancer cell lines in this study. Among the tested compounds, a benzothiazole derivative BSN-009 inhibited colon cancer cell lines growth by 57.53% by comparing the activity to the control drug aprepitant. Molecular modeling studies such as molecular docking and pharmacophore generation were performed with known NK1R antagonists and BSN-009 by using Discovery Studio 3.5 in order to explain their binding modes to NK1R. BSN-009 may be a good anticancer drug candidate as a possible NK1R antagonist and is worthy to carry on the anticancer studies.

The hit-to-lead optimization of 1,2,3,4,4a,9a-hexahydro-1H-xanthenes as glucocorticoid receptor antagonists

The structure–activity relationship（SAR） study of a 1 2 3 4 4a 9a-hexahydro-1H-xanthene series of selective,human glucocorticoid receptor a（hGRa） antagonists is reported.Compounds were screened using hydroxyapatite-based GR binding and MMTV-Luc co-transfection reporter gene assays.Four different regions of the scaffold were modified to assess the effects on hGRa antagonism and related potency.Compound 8d exhibits an 8-fold better bioactivity than the original hit 1a,as well as an improved chemical stability,which make it a promising lead for the subsequent optimization.