Hongjiang Xu

The highly potent and selective dipeptidyl peptidase IV inhibitors bearing a thienopyrimidine scaffold effectively treat type 2 diabetes

New dipeptidyl peptidase IV inhibitors were designed based on Alogliptin using a scaffold-hopping strategy. All of the compounds constructed on a thienopyrimidine scaffold demonstrated good inhibition and selectivity for DPP-IV. Compound 10d exhibited subnanomolar (IC(50)=0.33nM) DPP-IV inhibitory activity, good in vivo efficacy and an acceptable pharmacokinetic profile. A pharmacokinetic-driven optimization of 10d may lead to a new class of clinical candidate DPP-IV inhibitors.

Highly potent dipeptidyl peptidase IV inhibitors derived from Alogliptin through pharmacophore hybridization and lead optimization

The superposition of the DPP-IV complex revealed that the butynyl group of Linagliptin can be freely switched with the cyanobenzyl group of Alogliptin. Thus, a pharmacophore hybridization of Alogliptin was initiated and led to a novel DPP-IV inhibitor, 11a. Although it did not exhibit the desired activity (IC50=0.2 μM), compound 11a acts as a lead compound, which triggered a resulting structural optimization and the formation of compound 11m. A novel series of potent DPP-IV inhibitors represented by compound 11m (IC50=0.4 nM) was ultimately obtained with a robust pharmacokinetic profile and superior in vitro and in vivo efficacy compared to Alogliptin.

Magnesium isoglycyrrhizinate blocks fructose-induced hepatic NF-κB/NLRP3 inflammasome activation and lipid metabolism disorder

&NA; Magnesium isoglycyrrhizinate as a hepatoprotective agent possesses immune modulation and anti‐inflammation, and treats liver diseases. But its effects on immunological‐inflammatory and metabolic profiles for metabolic syndrome with liver injury and underlying potential mechanisms are not fully understood. In this study, magnesium isoglycyrrhizinate alleviated liver inflammation and lipid accumulation in fructose‐fed rats with metabolic syndrome. It also suppressed hepatic inflammatory signaling activation by reducing protein levels of phosphorylation of nuclear factor‐kappa B p65 (p‐NF‐&kgr;B p65), inhibitor of nuclear factor kappa‐B kinase &agr;/&bgr; (p‐IKK&agr;/&bgr;) and inhibitor of NF‐&kgr;B &agr; (p‐I&kgr;B&agr;) as well as nucleotide‐binding domain (NOD)‐like receptor protein 3 (NLRP3), apoptosis‐associated speck‐like protein (ASC) and Caspase‐1 in rats, being consistent with its reduction of interleukin‐1&bgr; (IL‐1&bgr;), tumor necrosis factor‐&agr; (TNF‐&agr;) and IL‐6 levels. Furthermore, magnesium isoglycyrrhizinate modulated lipid metabolism‐related genes characterized by up‐regulating peroxisome proliferator‐activated receptor‐&agr; (PPAR‐&agr;) and carnitine palmitoyl transferase‐1 (CPT‐1), and down‐regulating sensor for fatty acids to control‐1 (SREBP‐1) and stearoyl‐CoA desaturase 1 (SCD‐1) in the liver of fructose‐fed rats, resulting in the reduction of triglyceride and total cholesterol levels. These effective actions were further confirmed in fructose‐exposed BRL‐3A and HepG2 cells. The molecular mechanisms underpinning these observations suggest that magnesium isoglycyrrhizinate may inhibit NF‐&kgr;B/NLRP3 inflammasome activation to reduce immunological‐inflammatory response, which in turn may prevent liver lipid metabolic disorder and accumulation under high fructose condition. Thus, blockade of NF‐&kgr;B/NLRP3 inflammasome activation and lipid metabolism disorder by magnesium isoglycyrrhizinate may be the potential therapeutic approach for improving fructose‐induced liver injury with metabolic syndrome in clinic. Graphical abstract Figure. No caption available. HighlightsMagnesium isoglycyrrhizinate ameliorated fructose‐induced metabolic syndrome with non‐alcoholic fatty liver disease.Magnesium isoglycyrrhizinate blocked fructose‐induced NF‐&kgr;B/NLRP3 inflammasome activation and lipid accumulation in vivo and in vitro.Magnesium isoglycyrrhizinate exhibited the regulatory mechanism of immunological‐inflammatory and metabolic profiles.

Discovery of potent dipeptidyl peptidase IV inhibitors through pharmacophore hybridization and hit-to-lead optimization

A novel dipeptidyl peptidase IV inhibitor hit (5, IC50=0.86 μM) was structurally derived from our recently disclosed preclinical candidate 4 by replacing the cyanobenzyl with a butynyl based on pharmacophore hybridization. A hit-to-lead optimization effort was then initiated to improve its potency. Most N-substituted analogs exhibited good in vitro activity, and compound 18o (IC50=1.55 nM) was identified to be a potent dipeptidyl peptidase IV inhibitor with a significantly improved pharmacokinetic properties (bioavailablity: 41% vs 82.9%; T1/2: 2h vs 4.9h).

C-Aryl glucoside SGLT2 inhibitors containing a biphenyl motif as potential anti-diabetic agents

A series of highly active C-aryl glucoside SGLT2 inhibitors containing a biphenyl motif were designed and synthesized for biological evaluation. Among the compounds tested, compound 16l demonstrated high inhibitory activity against SGLT2 (IC50=1.9 nM) with an excellent pharmacokinetic profile. Further study indicated that the in vivo efficacy of compound 16l was comparable to that of dapagliflozin, suggesting that further development would be worthwhile.

Dataset on assessment of magnesium isoglycyrrhizinate injection for dairy diet and body weight in fructose-induced metabolic syndrome of rats

The data presented herein are related to the research article entitled “Magnesium isoglycyrrhizinate blocks fructose-induced hepatic NF-κB/NLRP3 inflammasome activation and lipid metabolism disorder” (Zhao et al., 2017) [1]. This article describes the effects of magnesium isoglycyrrhizinate on 24-h food or water intake in fructose-fed rats at 15-week. In addition, this article expands the effect of magnesium isoglycyrrhizinate on the animal body weight change during 1–17 week. The field dataset is made publicly available to enable critical or extended analyzes.

Structure-activity relationship study of a series of caspase inhibitors containing γ-amino acid moiety for treatment of cholestatic liver disease

A series of caspase inhibitors containing γ-amino acid moiety have been synthesized. A systemic study on their structure-activity relationship of anti-apoptotic cellular activity is presented. These efforts led to the discovery of compound 20o as a potent caspase inhibitor, which demonstrated preclinical ameliorating total bilirubin efficacy with a significantly improved pharmacokinetic profile.

TQ-B3203, a potent proliferation inhibitor derived from camptothecin

To develop topoisomerase I targeted drug candidates with sophisticated liposolubility, a series of novel camptothecin derivatives were synthesized through structure-based molecular hybridization and prodrug design approach. The compounds were used as compositions in micellar emulsion preparations, and the antiproliferative efficacy of these preparations were evaluated in two cancer cell lines (A2780s and A549) in vitro. The designed molecules were afterwards optimized for better potency by modifications at the aliphatic chain, the linker and the camptothecin-yl group to reach the optimal structure 7c (TQ-B3203), an SN-38 (camptothecin derivative, 7-ethyl-camptothecin-10-yl) containing compound. 7c showed excellent capacity of inhibiting cell proliferation with IC50 value at nanomolar level, and the potency was further confirmed in other human cancer cell lines (HT-29 and HePG2) superior to the positive reference irinotecan. 7c can be a promising candidate as antitumor drug. Its micellar emulsion preparation has succeeded in the preclinical studies and is in process for investigational new drug(IND) application.

Identification, characterization, and synthesis of process-related impurities in antiproliferative agent TQ-B3203

ABSTRACT Liposoluble camptothecin derivative, research name TQ-B3203, is a recently developed investigational antiproliferative agent by our group. The structure of TQ-B3203 is 2-(hexadecyloxycarbonyl)-2,5,7,8-tetramethylchroman-6-yl 7-ethyl-camptothecin-10-yl succinate, containing an SN-38 component, a trolox component, a succinic acid linker, and a hexadecanol chain. In this study, the process-related impurities of bulk TQ-B3203 were identified, characterized, and synthesized. Seven major impurities were revealed based on the mass spectrum (MS) and nuclear magnetic resonance (NMR) spectral data. They were characterized as SN-38 (IMP-I), trolox (IMP-II), 2-(dodecyloxycarbonyl)-2,5,7,8-tetramethylchroman-6-yl 7-ethyl-camptothecin-10-yl succinate (IMP-III), hexadecyl 7-ethyl-camptothecin-10-yl succinate (IMP-IV), 2-(tetradecyloxycarbonyl)-2,5,7,8-tetramethylchroman-6-yl 7-ethyl-camptothecin-10-yl succinate (IMP-V), 4-(2-(hexadecyloxycarbonyl)-2,5,7,8-tetramethylchroman-6-yloxy)-4-oxobutanoic acid (IMP-VI), and 4-(2-(octodecyloxycarbonyl)-2,5,7,8-tetramethylchroman-6-yloxy)-4-oxobutanoic acid (IMP-VII). The probable origin of the impurities from the preparation process of TQ-B3203 was discussed. GRAPHICAL ABSTRACT