[Design, synthesis and structure-activity relationship studies of human dihydroorotate dehydrogenase inhibitors].

In this study, 1-(3-(4-chlorophenyl)-5-methylthio-1H-1,2,4-triazol-1-yl)-butan-1-one discovered previously in our lab was selected as a inhibitor of human dihydroorotate dehydrogenase ( HsDHODH) for structural optimization. The co-crystal of HsDHODH with the hit was obtained and analyzed for guiding the subsequent structural optimization. As a result, a series of novel triazole derivatives were designed and synthesized as potent HsDHODH inhibitors. Among them, compound (3-(4-chlorophenyl)-5-ethylthio-1H- 1,2,4-triazol-1-yl)-furan-2-yl-methanone displayed high potency in the inhibition of HsDHODH with an IC50 value of 1.50 µmol·L−1. Meanwhile, the structure-activity relationships were analyzed based on the biological data and the co-crystal structure. These results provide a valuable reference for optimization of 1H-1,2,4- triazole derivatives as HsDHODH inhibitors in the future.

Thoracic Endovascular Aortic Repair versus Optimal Medical Treatment in Patients with Type B Intramural Hematoma: A Meta-Analysis.

PURPOSE: We intended to study the effect of thoracic endovascular aortic repair (TEVAR) and optimal medical treatment (OMT) on type B intramural hematoma (BIMH). METHODS: We searched PubMed, EMbase, Cochrane Library, and China National Knowledge Infrastructure databases that compared TEVAR and OMT in patients with BIMH. Two authors independently assessed the risk of bias using the Newcastle-Ottawa Scale. The rate ratio (RR) and 95% confidence interval were used to calculate the outcome. The primary endpoints were aortic-related death and regression/resolution. Secondary endpoints were all-cause death, progression to dissection, and secondary intervention. RESULTS: Eight observational studies were included in the analysis. TEVAR reduced aortic-related death (RR 0.22, 95% CI 0.08-0.56, P = 0.002, I² = 24%) and promoted hematoma regression/resolution (RR 1.48, 95% CI 1.05-2.10, P <0.05, I² = 71%) compared to OMT. Moreover, TEVAR was associated with a reduction in progression to dissection (RR 0.32, 95% CI 0.13-0.81, P <0.02, I² = 39%) and secondary intervention (RR 0.18, 95% CI 0.09-0.37, P <0.00001, I² = 38%) compared to OMT. However, all-cause death has no significant difference between the two groups (RR 0.45, 95% CI 0.17-1.19, P = 0.11, I² = 58%). CONCLUSIONS: The results of this meta-analysis suggested that TEVAR is an effective treatment for BIMH, which can delay the progression of intramural hematoma and promotes regression/resolution. More research about indications of TEVAR is still needed.

Efficacy and safety of rivaroxaban plus clopidogrel versus aspirin plus clopidogrel in patients with coronary atherosclerotic heart disease and gastrointestinal disease undergoing percutaneous coronary intervention: study protocol for a non-inferiority randomized controlled trial.

BACKGROUND: Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor is recommended for patients with coronary heart disease (CHD) undergoing percutaneous coronary intervention (PCI) to antithrombosis, meanwhile, increasing the risks of gastrointestinal bleeding. Rivaroxaban, a novel oral anticoagulant, combined with a P2Y12 receptor inhibitor reduces adverse events in patients with CHD and atrial fibrillation who underwent PCI. The effect of rivaroxaban plus P2Y12 inhibitor on reducing bleeding events in patients with CHD and gastrointestinal disease (GID) undergoing PCI remains unclear. METHOD: The study is a prospective, single-center, randomized controlled trial. A total of 1020 patients with CHD and GID undergoing PCI will be enrolled. Patients are randomized (1:1) to receive either rivaroxaban 10 mg plus clopidogrel 75 mg daily or aspirin 100 mg plus clopidogrel 75 mg daily; both treatments will last 6 months. The primary endpoint is Bleeding Academic Research Consortium (BARC) type 2-5 bleeding requiring medical intervention. The secondary endpoint is a composite of major adverse cardiovascular and cerebrovascular events (MACCE), including all-cause death, cardiac death, nonfatal myocardial infarction, stent thrombosis, ischemia-driven target vessel revascularization, and stroke. DISCUSSION: The objective of this study is to evaluate the efficacy and safety of rivaroxaban plus clopidogrel versus aspirin plus clopidogrel in patients with CHD and GID undergoing PCI. We aim to explore an optimized antithrombotic strategy, which achieves the same anti-ischemic effect as standard DAPT without increasing the risk of GIB, for patients with CHD and GID undergoing PCI. TRIAL REGISTRATION: This protocol is registered at the Chinese Clinical Trial Registry under the number ChiCTR2100044319. And this publication is based on version 1.4 of the trial protocol dated Sep 6, 2021.

Clinical Associations of Preoperative and Postoperative Serum CEA and Lung Cancer Outcome.

Background: Serum carcinoembryonic antigen (CEA), a classic tumour marker, is widely used in lung cancer in clinical practice. Nevertheless, few studies have elucidated the influence of dynamic changes in CEA in the perioperative phases, as a prognostic indicator, on lung cancer prognosis. Methods: This retrospective cohort analysis included consecutive patients with stage I-III lung cancer who underwent curative resection between December 2010 and December 2014. The patients were grouped into three cohorts: group A included patients with normal preoperative CEA, group B included patients with elevated preoperative CEA but normal postoperative CEA, and group C included patients with elevated preoperative and postoperative CEA. Five-year overall survival (OS) was estimated by Kaplan-Meier analysis (log-rank test). Multivariate analyses were performed with Cox proportional hazard regression. Results: A total of 1662 patients with stage I-III lung cancer were enrolled in our study. Patients with normal preoperative CEA had 15.9 and 20.1% better 3- and 5-year OS rates than the cohort with elevated preoperative CEA (p < 0.001). Furthermore, group C had 36.0 and 26.6% lower 5-year OS rates (n = 74, 32.4%) than group A (n = 1188, 68.4%) and group B (n = 139, 59.0%) (p < 0.001). Group B had poorer OS than group A (p = 0.016). For patients with different pathological TNM stages, subgroup analyses showed that group C had the shortest OS in stages I and II (p < 0.05), and patients with a post-preoperative CEA increment had poorer OS than those without an increment (p = 0.029). Multivariate analyses suggested that group C (HR = 2.0, 95% CI, 1.5-2.7, p < 0.001) rather than the group with normalized postoperative CEA (HR = 1.2, 95% CI, 0.9-1.5, p = 0.270) was an independent prognostic factor. In subgroup analysis of adenocarcinoma (ADC), survival analyses suggested that group C predicted a worse prognosis. Multivariate analysis of ADC indicated that group C was an independent adverse prognostic factor (HR = 1.9, 95% CI, 1.4-2.7, p < 0.001). Conclusions: Combined elevated preoperative and postoperative CEA is an independent adverse prognostic factor for stage I-III lung adenocarcinoma. Additionally, routine perioperative detection of serum CEA can yield valuable prognostic information for patients after lung cancer surgery.

Discovery and Rational Design of Natural-Product-Derived 2-Phenyl-3,4-dihydro-2H-benzo[f]chromen-3-amine Analogs as Novel and Potent Dipeptidyl Peptidase 4 (DPP-4) Inhibitors for the Treatment of Type 2 Diabetes.

Starting from the lead isodaphnetin, a natural product inhibitor of DPP-4 discovered through a target fishing docking based approach, a series of novel 2-phenyl-3,4-dihydro-2H-benzo[f]chromen-3-amine derivatives as potent DPP-4 inhibitors are rationally designed utilizing highly efficient 3D molecular similarity based scaffold hopping as well as electrostatic complementary methods. Those ingenious drug design strategies bring us approximate 7400-fold boost in potency. Compounds 22a and 24a are the most potent ones (IC50 ≈ 2.0 nM) with good pharmacokinetic profiles. Compound 22a demonstrated stable pharmacological effect. A 3 mg/kg oral dose provided >80% inhibition of DPP-4 activity within 24 h, which is comparable to the performance of the long-acting control omarigliptin. Moreover, the efficacy of 22a in improving the glucose tolerance is also comparable with omarigliptin. In this study, not only promising DPP-4 inhibitors as long acting antidiabetic that are clinically on demand are identified, but the target fish docking and medicinal chemistry strategies were successfully implemented.