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.

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%.

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.

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.

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.

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.

Synthesis and biological evaluation of novel phenothiazine derivatives as non-peptide arginine vasopressin V2 receptor antagonists

A series of novel phenothiazine derivatives was synthesized and tested for arginine vasopressin receptor antagonist activity. They were synthesized as novel arginine vasopressin receptor antagonists from phenothiazine as a scaffold via successive acylation, reduction and acylation reactions. Their structures were characterized by ^1H NMR, ^13C NMR and HRMS, and biological activity was evaluated by in vitro and in vivo studies. The in vitro binding assay indicated that several compounds are potent selective V2 receptor antagonists. Compounds with promising binding affinity to V2 receptors were selected to conduct the in vivo diuretic studies on Sprague-Dawley rats. Among them, 1n, 1r, It and 1v exhibited excellent diuretic activity, especially 1 r and 1v. Therefore, 1 r and 1v are potent novel AVP V2 receptor antagonist candidates.

Efficacy and anti-inflammatory analysis of glucocorticoid,antihistamine and leukotriene receptor antagonist in the treatment of allergic rhinitis

BACKGROUND There are many adverse reactions in the treatment of allergic rhinitis(AR)mainly with conventional drugs.Leukotriene receptor antagonists,glucocorticoids and nasal antihistamines can all be used as first-line drugs for AR,but the clinical effects of the three drugs are not clear.AIM To examine the impact of glucocorticoids,antihistamines,and leukotriene receptor antagonists on individuals diagnosed with AR,specifically focusing on their influence on serum inflammatory indexes.METHODS The present retrospective study focused on the clinical data of 80 patients diagnosed and treated for AR at our hospital between May 2019 and May 2021.The participants were categorized into the control group and the observation group.The control group received leukotriene receptor antagonists,while the observation group was administered glucocorticoids and antihistamines.Conducted an observation and comparison of the symptoms,physical sign scores,adverse reactions,and effects on serum inflammatory indexes in two distinct groups of patients,both before and after treatment.RESULTS Subsequent to treatment,the nasal itching score,sneeze score,runny nose score,nasal congestion score,and physical signs score exhibited notable discrepancies(P<0.05),with the observation group demonstrating superior outcomes compared to the control group(P<0.05).The interleukin(IL)-6,IL-10,tumor necrosis factor-alpha,Soluble Intercellular Adhesion Molecule-1,Leukotriene D4 after treatment were significantly different and the observation group It is better than the control group,which is statistically significant(P<0.05).Following the intervention,the incidence of adverse reactions in the observation group,including symptoms such as nasal dryness,discomfort in the throat,bitter taste in the mouth,and minor erosion of the nasal mucosa,was found to be 7.5%.This rate was significantly lower compared to the control group,which reported an incidence of 27.5%.The difference between the two groups was statistically significant(P<0.05).CONCLUSION Glucocorticoids and antihistamines have obvious therapeutic effects,reduce serum inflammatory index levels,relieve symptoms and signs of patients,and promote patients'recovery,which can provide a reference for clinical treatment of AR.

Medical therapy for clinical benign prostatic hyperplasia:α1 Antagonists,5α reductase inhibitors and their combination

Medical therapy for clinical benign prostatic hyperplasia(BPH)has advanced significantly in the last 2 decades.Many new a1 antagonists and 5a reductase inhibitors(5ARi)are now commercially available.The practicing urologist must decide on the most appropriate medication for his patients,taking into consideration various factors like efficacy,dosing regime,adverse effects,cost,patient’s socioeconomic background,expectations,drug availability and his own clinical experience.The use of combination therapy added further to the complexity in clinical judgment when prescribing.We highlight some of the key points in prescribing a1 antagonists,5ARi and their combination,based on our viewpoints and experience as urologists in an Asian clinical setting.

Hypoxia inducible factor 1α promotes interleukin-1 receptor antagonist expression during hepatic ischemia-reperfusion injury

BACKGROUND Ischemia-reperfusion injury(IRI) is a major risk associated with liver surgery and transplantation,and its pathological mechanism is complex.Interleukin-1 receptor antagonist(IL-1ra) can protect the liver from IRI.However,the regulatory mechanism of IL-1ra expression is still unclear.AIM To identify the mechanism that could protect the liver in the early stage of IRI.METHODS To screen the key genes in hepatic IRI,we performed RNA sequencing and gene enrichment analysis on liver tissue from mice with hepatic IRI.Subsequently,we verified the expression and effect of IL-1ra in hepatic IRI.We also used promoter mutagenesis and chromatin immunoprecipitation assay to search for the transcriptional regulatory sites of hypoxia-inducible factor(HIF)-1α.Finally,to explore the protective mechanism of ischemic preconditioning(IP),we examined the expression of HIF-1α and IL-1ra after IP.RESULTS We identified IL-1ra as a key regulator in hepatic IRI.The expression of IL-1ra was significantly upregulated after hepatic IRI both in vivo and in vitro.Furthermore,we found that HIF-1αregulated Il-1ra transcription in response to hypoxia.Increased HIF-1α accumulation promoted IL-1ra expression,whereas inhibition of HIF-1α exhibited the opposite effect.We also confirmed a predominant role for hypoxia response element in the regulation of Il1ra transcription by HIF-1αactivation.Of note,we demonstrated that IP protects against hepatic IRI by inducing IL-1ra expression,which is mediated through HIF-1α.CONCLUSION We demonstrated that ischemia or hypoxia leads to increased expression of IL-1ra through HIF-1α.Importantly,IP protects the liver from IRI via the HIF-1α–IL-1ra pathway.