Chunlei Tang

Interleukin-23: as a drug target for autoimmune inflammatory diseases

Interleukin‐23 (IL‐23) is a member of the IL‐12 family of cytokines with pro‐inflammatory properties. Its ability to potently enhance the expansion of T helper type 17 (Th17) cells indicates the responsibility for many of the inflammatory autoimmune responses. Emerging data demonstrate that IL‐23 is a key participant in central regulation of the cellular mechanisms involved in inflammation. Both IL‐23 and IL‐17 form a new axis through Th17 cells, which has evolved in response to human diseases associated with immunoactivation and immunopathogeny, including bacterial or viral infections and chronic inflammation. Targeting of IL‐23 or the IL‐23 receptor or IL‐23 axis is a potential therapeutic approach for autoimmune diseases including psoriasis, inflammatory bowel disease, rheumatoid arthritis and multiple sclerosis. The current review focuses on the immunobiology of IL‐23 and summarizes the most recent findings on the role of IL‐23 in the pre‐clinical and ongoing clinical studies.

The first pharmacophore model for potent G protein-coupled receptor 119 agonist

G protein-coupled receptor 119 (GPR119) has emerged as arguably one of the most exciting targets for the treatment of type 2 diabetes mellitus in the new millennium. Pharmacophore models were developed by using Discovery Studio V2.1 with a training set of 24 GPR119 agonists. The best hypothesis consisting of five features, namely, two hydrogen bond acceptors and three hydrophobic features, has a correlation coefficient of 0.969, cost difference of 62.68, RMS of 0.653, and configuration cost of 15.24, suggesting that a highly predictive pharmacophore model was successfully obtained. The application of the model shows great success in predicting the activities of the 25 known GPR119 agonists in our test set with a correlation coefficient of 0.933.

Design, Synthesis, and Biological Evaluation of Andrographolide Derivatives as Potent Hepatoprotective Agents

Poor water solubility limits the clinical use of andrographolide and its derivatives. In an attempt to develop potent hepatoprotective drugs, a strategy was proposed to improve the aqueous solubility of andrographolide. Ten andrographolide derivatives were designed, synthesized, evaluated for aqueous solubility and in vivo hepatoprotective activity against CCl4‐induced liver injury in mice. As expected, the aqueous solubility of synthetic derivatives was effectively improved. All compounds demonstrated the effect of different degrees in improving the liver enzyme (ALT and AST) activity, especially the most promising compound 9d significantly improved liver enzyme activity, with high potency to be a new lead.

Synthesis and biological evaluation of andrographolide derivatives as potent anti-HIV agents.

In an attempt to develop potent anti‐HIV drugs, 20 andrographolide derivatives were designed, synthesized, and evaluated for their in vitro anti‐HIV activity. The screening results revealed that five compounds showed potent anti‐HIV activities with therapeutic indices (TI) above 10. The most promising compound 6f shows a significant TI close to 34.07, with the potency to be a new lead.

A specific pharmacophore model of sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors

Sodium-dependent glucose co-transporter 2 (SGLT2) plays a pivotal role in maintaining glucose equilibrium in the human body, emerging as one of the most promising targets for the treatment of diabetes mellitus type 2. Pharmacophore models of SGLT2 inhibitors have been generated with a training set of 25 SGLT2 inhibitors using Discovery Studio V2.1. The best hypothesis (Hypo1SGLT2) contains one hydrogen bond donor, five excluded volumes, one ring aromatic and three hydrophobic features, and has a correlation coefficient of 0.955, cost difference of 68.76, RMSD of 0.85. This model was validated by test set, Fischer randomization test and decoy set methods. The specificity of Hypo1SGLT2 was evaluated. The pharmacophore features of Hypo1SGLT2 were different from the best pharmacophore model (Hypo1SGLT1) of SGLT1 inhibitors we developed. Moreover, Hypo1SGLT2 could effectively distinguish selective inhibitors of SGLT2 from those of SGLT1. These results indicate that a highly predictive and specific pharmacophore model of SGLT2 inhibitors has been successfully obtained. Then Hypo1SGLT2 was used as a 3D query to screen databases including NCI and Maybridge for identifying new inhibitors of SGLT2. The hit compounds were subsequently subjected to filtering by Lipinski’s rule of five. And several compounds selected from the top ranked hits have been suggested for further experimental assay studies.

3D QSAR Pharmacophore Modeling for c-Met Kinase Inhibitors

The receptor tyrosine kinase c-Met has multiple roles during cancer development and is currently considered as a promising target for cancer therapies. Pharmacophore models of c-Met kinase inhibitors have been developed based on 22 diverse compounds by using HypoGen algorithm implemented in Discovery studio program package. The best quantitative pharmacophore model, Hypo 1, which had the highest correlation coefficient (0.9623), consists of two hydrogen bond acceptors, one hydrophobic feature and two excluded volumes. Then best model was validated by test set prediction, Fischer randomization and decoy set. Besides, the features of Hypo1 were verified to correctly reflect the interactions between kinase active site and its ligands by comparison and superimposition of Hypo 1 in active site of c-Met kinase. The results shows that Hypo 1 has strong capability to identify c-Met kinase inhibitors and to predict the activities of structurally diverse molecules. Therefore, our pharmacophore models were considered as valuable tools for the discovery and development of specific c-Met kinase inhibitors.

Synthesis and preliminary antihyperlipidaemic activities evaluation of andrographolide derivatives.

Recent studies indicated that andrographolide was a potential antihyperlipidaemic therapeutic agent. In the paper, the synthesis of a series of andrographolide derivatives was described and their antihyperlipidaemic activities were evaluated in vivo. As compared with TG, TC, HDL-C and LDL-C concentrations, some of the derivatives exhibited better antihyperlipidaemic effects than positive control atromide. Therein, compound 6i, which was the most potent compound, could serve as a new lead for further development of antihyperlipidaemic agents.

Zebrafish as a New Model for Phenotype-based Screening of Positive Inotropic Agents

The zebrafish‐based assay is a widely used animal model system for cardiovascular research. In this study, we investigated the cardiac defects caused by terfenadine and tested the pharmacological response of digoxin to zebrafish with cardiac defects. The study suggested that zebrafish could be a suitable model for phenotype‐based screening and evaluation of positive inotropic agents. This phenotype‐based heart failure zebrafish model system was then utilized in in‐house library screen. Some positive inotropic compound was discovered, which could attenuate the cardiac defects by increasing the flow velocity of caudal artery blood.

Discovery, synthesis and evaluation of novel cholesterol absorption inhibitors.

Chemical‐based common feature pharmacophore modelling of Niemann Pick C1 Like 1 inhibitors was performed to provide some insights on the important pharmacophore features essential for Niemann Pick C1 Like 1 inhibition using Discovery Studio V2.5. After in‐house database screening, a new series of substituted oxazolidinones, selected from the top ranked hits, have been synthesized and evaluated as novel cholesterol absorption inhibitors. All compounds demonstrated effect of different degrees in lowering the total cholesterol in serum, especially compounds 1a, 2a and 2d, the potency of which was comparable to that of ezetimibe. It was also found that 1a, 1d and 2d could raise high‐density lipoprotein cholesterol levels markedly. Interestingly, compounds 2a–2f appeared to have the moderate potential to lower triglyceride levels, which were superior to that of normal cholesterol absorption inhibitors including ezetimibe.

Design, synthesis, and biological evaluation of 2-(4-(methylsulfonyl)phenyl)pyridine derivatives as GPR119 agonists

This study describes the design, synthesis, and biological evaluation of a series of novel small molecule GPR119 agonists with improved potency and moderate physiochemical characteristics. Among them, the most promising compounds 19 and 20 were obtained with EC50 values of 75 and 25 nM, respectively, in vitro cAMP assays and effectively decreased blood glucose excursion in oral glucose tolerance test (OGTT) of normal mice. Furthermore, in OGTT with type 2 diabetic mice induced by streptozotocin and high‐fat diet, compound 19 also showed significant reduction in blood glucose level compared to vehicle control group, which demonstrated an attractive in vitro and in vivo profile for further development.