Shanghai Hengrui Pharmaceuticals Co.

Shanghai, China

Shanghai Hengrui Pharmaceuticals Co.

Shanghai, China
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Begley D.W.,University of Washington | Begley D.W.,Emerald Biostructures | Zheng S.,University of Washington | Zheng S.,Shanghai Hengrui Pharmaceuticals Co. | Varani G.,University of Washington
Chemical Biology and Drug Design | Year: 2010

Solution-state nuclear magnetic resonance (NMR) is a versatile tool for the study of binding interactions between small molecules and macromolecular targets. We applied ligand-based NMR techniques to the study of human thymidylate synthase (hTS) using known nanomolar inhibitors and a library of small molecule fragments. Screening by NMR led to the rapid identification of ligand pairs that bind in proximal sites within the cofactor-binding pocket of hTS. Screening hits were used as search criteria within commercially available sources, and a subset of catalog analogs were tested for potency by in vitro assay and binding affinity by quantitative saturation transfer difference (STD)-NMR titration. Two compounds identified by this approach possess low micromolar affinity and potency, as well as excellent binding efficiency against hTS. Relative binding orientations for both leads were modeled using AutoDock, and the most likely bound conformations were validated using experimentally derived STD-NMR binding epitope data. These ligands represent novel starting points for fragment-based drug design of non-canonical TS inhibitors, and their binding epitopes highlight important and previously unexploited interactions with conserved residues in the cofactor-binding site. © 2010 John Wiley & Sons A/S.

Liu X.,CAS Shanghai Institute of Materia Medica | Zhang L.-N.,CAS Shanghai Institute of Materia Medica | Feng Y.,CAS Shanghai Institute of Materia Medica | Zhang L.,Shanghai Hengrui Pharmaceuticals Co. | And 3 more authors.
Acta Pharmacologica Sinica | Year: 2012

Aim:Dipeptidyl deptidase-4 (DPP-4) inhibitors are a new class of anti-diabetic agents. The purpose of this study was to assess the acute and chronic effects of SHR117887, a novel DPP-4 inhibitor, on metabolic control and pancreatic Β-cell function in normal or diabetic rodent models.Methods:In the acute experiments, ICR mice, diet-induced obese (DIO) rats and ob/ob mice were subjected to an oral glucose tolerance test (OGTT) following a single oral administration of SHR117887 (0.1, 0.3, 1 or 3 mg/kg). Blood samples were collected to measure glucose, insulin, DPP-4 activity and active GLP-1 level. In the chronic experiments, ob/ob mice was administered SHR117887 (3, 10 or 30 mg/kg) twice daily for 33 d to assess the effects on metabolic control and pancreatic Β-cell function. Vildagliptin (LAF237) was used as a positive control in all the experiments.Results:Acute oral administration of SHR117887 dose-dependently decreased the serum DPP-4 activity and improved glucose tolerance in ICR mice, DIO rats and ob/ob mice. This was accompanied by significant increases in the serum active GLP-1 and insulin levels. Chronic administration of SHR117887 significantly decreased fasting blood glucose level and improved the lipid profiles in ob/ob mice by reducing the serum triglyceride and free fatty acid levels, and its efficacy was comparable with that of vildagliptin at the same molarity. Moreover, chronic administration of SHR117887 increased the insulin staining of islet cells, which is suggestive of improved Β-cell function.Conclusion:SHR117887 is a potent DPP-4 inhibitor that improves metabolic control and Β-cell function in diabetic rodent models, suggesting that it could be a new therapeutic agent for the treatment of type 2 diabetes. © 2012 CPS and SIMM. All rights reserved.

Yan P.-K.,CAS Shanghai Institute of Materia Medica | Zhang L.-N.,CAS Shanghai Institute of Materia Medica | Feng Y.,CAS Shanghai Institute of Materia Medica | Qu H.,CAS Shanghai Institute of Materia Medica | And 3 more authors.
Acta Pharmacologica Sinica | Year: 2014

Aim: The sodium glucose cotransporter 2 (SGLT2) plays an important role in renal glucose reabsorption, thus serves as a new target for the treatment of diabetes. The purpose of this study was to evaluate SHR3824 as a novel selective SGLT2 inhibitor and to characterize its in vivo effects on glucose homeostasis. The effects of chronic administration of SHR3824 on peripheral insulin sensitivity and pancreatic β-cell function were also investigated. Methods: The in vitro potency and selectivity of SHR3824 were assessed in HEK293 cells transfected with human SGLT2 or SGLT1. Acute and multi-dose studies were performed on ICR mice, GK rats and db/db mice to assess the ability of SHR3824 to enhance urinary glucose excretion and improve blood glucose levels. 2-Deoxyglucose uptake and insulin immunohistochemical staining were performed in the soleus muscle and pancreas, respectively, of db/db mice. A selective SGLT2 inhibitor BMS512148 (dapagliflozin) was taken as positive control. Results: SHR3824 potently inhibited human SGLT2 in vitro, but exerted much weak inhibition on human SGLT1 (the IC50 values of SHR3824 against human SGLT2 and SGLT1 were 2.38 and 4324 nmol/L, respectively). Acute oral administration of SHR3824 (0.3, 1.0, 3.0 mg/kg) dose-dependently improved glucose tolerance in ICR mice, and reduced hyperglycemia by increasing urinary glucose excretion in GK rats and db/db mice. Chronic oral administration of SHR3824 (0.3, 1.0, 3.0 mg·kg-1·d-1) dose-dependently reduced blood glucose and HbA1c levels in GK rats and db/db mice, and significantly increased insulin-stimulated glucose uptake in the soleus muscles and enhanced insulin staining in the islet cells of db/db mice. Conclusion: SHR3824 is a potent and selective SGLT2 inhibitor and exhibits antidiabetic efficacy in several rodent models, suggesting its potential as a new therapeutic agent for the treatment of type 2 diabetes. © 2014 CPS and SIMM All rights reserved.

Wei Z.,Fudan University | Wei Z.,Key Laboratory of Smart Drug Delivery | Yuan S.,Shanghai Hengrui Pharmaceuticals Co. | Hao J.,Fudan University | And 3 more authors.
European Journal of Pharmaceutics and Biopharmaceutics | Year: 2013

The aim of this study was to clarify the relationship between the concentration of Pluronic P123/F127 block copolymers and P-glycoprotein (P-gp) inhibitory potency. Modulation of multidrug resistance (MDR) by Pluronic P123/F127 was evaluated in P-gp over-expressing human breast cancer cell line MCF-7/ADR and its non-P-gp over-expressing counterpart MCF-7 cells. Four different probes (known as P-gp substrates) including rhodamine 123 (R-123), rhodamine 6G (R-6G), doxorubicin (DOX), and paclitaxel (PTX) were applied to investigate the impact of Pluronic P123/F127 copolymers with different concentrations on the intracellular accumulation of these probes. Additionally, the intracellular ATP and mitochondrial transmembrane potential in MCF-7/ADR cells were determined over a wide concentration range of Pluronic P123/F127. Furthermore, the endocytic mechanisms of Pluronic micelles were performed. It was suggested that P-gp substrate hydrophobicity and the concentration of P123/F127 copolymers had little impact on P-gp inhibitory activity of Pluronic P123/F127 itself. Intracellular ATP depletion was the main mechanism of Pluronic P123/F127 for P-gp inhibition. In vitro cytotoxicity study was also conducted in order to compare cytotoxic effect among different PTX formulations. It indicated that the IC50 of PTX-loaded Pluronic P123/F127 mixed micelles was 6.3-fold lower than free PTX and 2.3-fold lower than Taxol, respectively. Therefore, Pluronic P123/F127 polymeric micelles could be considered a promising drug delivery system to overcome MDR in cancer therapy. © 2012 Elsevier B.V. All rights reserved.

Zhang W.,Fudan University | Shi Y.,Shanghai Hengrui Pharmaceuticals Co. | Chen Y.,Fudan University | Ye J.,Fudan University | And 2 more authors.
Biomaterials | Year: 2011

The aim of this study was to exploit the possibility of combination of active targeting function of folic acid by folate receptor-mediated endocytosis and overcoming multidrug resistance (MDR) by Pluronic block copolymers to promote drug delivery to MDR tumor following intravenous administration with paclitaxel (PTX) as model drug. Folic acid functionalized Pluronic P123/F127 mixed micelles encapsulating PTX (FPF-PTX) was firstly developed and tested in vitro and in vivo, while PTX-loaded Pluronic P123/F127 mixed micelles (PF-PTX) and Taxol were used as control. FPF-PTX was about 20 nm in diameter with spherical shape and high encapsulation efficiency. Cellular uptake of FPF-PTX was found to be higher than that of PF-PTX due to the folate receptor-mediated endocytosis effect. In vitro cytotoxicity, cell apoptosis and cell cycle arrest studies also revealed that FPF-PTX was more potent than those of PF-PTX and Taxol. In vivo pharmacokinetic study in rats showed that the polymeric micelles significantly enhanced the bioavailability of PTX (∼3 fold) than Taxol. Moreover, in BALB/c mice bearing KBv MDR tumor xenografts, stronger antitumor efficacy was shown in FPF-PTX group, with good correlation between in vitro and in vivo. In conclusion, folate-conjugated Pluronic micelles could be a potential vehicle for delivering hydrophobic chemotherapeutic drugs to MDR tumors. © 2010.

Zhang W.,Fudan University | Shi Y.,Shanghai Hengrui Pharmaceuticals Co. | Chen Y.,Fudan University | Hao J.,Fudan University | And 2 more authors.
Biomaterials | Year: 2011

The increasing global incidence of malignant melanoma combined with the poor prognosis and low survival rates of patients necessitates the development of new chemotherapeutic strategies. Thus, the objective of this present study was to investigate the therapeutic efficacy of Pluronic polymeric micelles encapsulating paclitaxel (PTX) in both B16F10 melanoma subcutaneous mice model and pulmonary metastatic mice model. Herein, we developed a PTX-loaded polymeric micelles (PF-PTX) consisting of Pluronic P 123 and F127 block copolymers with small particle size (∼25 nm), high encapsulation efficiency (>90%), good stability in lyophilized form and pH-dependent in vitro release. Furthermore, influence of PF-PTX on in vitro cytotoxicity was determined by MTT assay using B16F10 melanoma cell line, while cellular distribution of PF-PTX was detected by confocal microscopy. Additionally, C57BL/6 mice bearing subcutaneous or pulmonary B16F10 melanoma tumors were treated with Taxol or PF-PTX, and antitumor effect was compared. It was found that antitumor efficacy of PF-PTX in both tumor models showed significant tumor growth delay and increased survival. In summary, the simple Pluronic-based nanocarrier could be harnessed for the delivery of anticancer drug to melanoma, with increased therapeutic index. © 2011 Elsevier Ltd.

Zhang W.,Fudan University | Shi Y.,Shanghai Hengrui Pharmaceuticals Co. | Chen Y.,Fudan University | Yu S.,Fudan University | And 4 more authors.
European Journal of Pharmaceutics and Biopharmaceutics | Year: 2010

The aim of this work was to demonstrate the advantage of using paclitaxel (PTX)-loaded Pluronic P123/F127 mixed micelles (PF-PTX) against non-small cell lung cancer (NSCLC) compared to Taxol. Modulation of multidrug resistance (MDR) by Pluronic mixed micelles was evaluated in lung resistance protein (LRP)-overexpressing human lung adenocarcinoma A-549 cell line. Influence of PF-PTX on in vitro cytotoxicity was determined by MTT assay, while cellular apoptosis was detected by cell nuclei staining and Annexin V-FITC apoptosis detection kit. Cell cycle arrest was also confirmed by flow cytometry. Additionally, in vivo fate and antitumor efficacy of PF-PTX were extensively evaluated in comparison with Taxol. It was demonstrated that PF-PTX had superior anti-proliferation activity against A-549 cells compared with Taxol as measured by IC 50. The enhanced anti-cancer efficacy of PF-PTX was associated with PTX-induced apoptosis and cell arrest in the G 2/M phase. Intracellular ATP depletion and decreased mitochondrial potential caused by Pluronic copolymers were found to be related to modulation of MDR. PF-PTX also exhibited significant advantages in pharmacokinetics and A-549 xenograft tumor model versus Taxol. The PF-PTX formulation achieved 3.0-fold longer mean residence time in circulation, 2.2-fold larger area under the plasma concentration-time curve than Taxol. At 28days, tumor volume in PF-PTX group was only 31.8% that of the Taxol. Therefore, PF-PTX significantly enhanced the anti-cancer activity of PTX and might be considered a promising drug delivery system to overcome MDR in lung cancer. © 2010.

Lu B.,University of California at Santa Barbara | Lu B.,Shanghai Hengrui Pharmaceuticals Co. | Li Y.,CAS Shanghai Institute of Organic Chemistry | Wang Y.,University of California at Santa Barbara | And 3 more authors.
Journal of the American Chemical Society | Year: 2013

Gold-catalyzed intramolecular oxidation of terminal alkynes with an arenesulfinyl group as the tethered oxidant is a reaction of high impact in gold chemistry, as it introduced to the field the highly valued concept of gold carbene generation via alkyne oxidation. The proposed intermediacy of α-oxo gold carbenes in these reactions, however, has never been substantiated. Detailed experimental studies suggest that the involvement of such reactive intermediates in the formation of dihydrobenzothiepinones is highly unlikely. Instead, a [3,3]-sigmatropic rearrangement of the initial cyclization intermediate offers a reaction path that can readily explain the high reaction efficiency and the lack of sulfonium formation. With internal alkyne substrates, however, the generation of a gold carbene species becomes competitive with the [3,3]-sigmatropic rearrangement. This reactive intermediate, nevertheless, does not proceed to afford the Friedel-Crafts-type cyclization product. Extensive density functional theory studies support the mechanistic conclusion that the cyclized product is formed via an intramolecular [3,3]-sigmatropic rearrangement instead of the previously proposed Friedel-Crafts-type cyclization. With the new mechanistic insight, the product scope of this versatile formation of mid-sized sulfur-containing cycloalkenones has been expanded readily to various dihydrobenzothiocinones, a tetrahydrobenzocyclononenone, and even those without the entanglement of a fused benzene ring. Besides gold, Hg(OTf)2 can be an effective catalyst, thereby offering a cheap alternative for this intramolecular redox reaction. © 2013 American Chemical Society.

Dong Q.,0410 Science Center Drive | Dong Q.,Shanghai Hengrui Pharmaceuticals Co | Dougan D.R.,0410 Science Center Drive | Gong X.,0410 Science Center Drive | And 8 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2011

A novel 5-phenylamino-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione series of MEK inhibitors has been developed using structure-based drug design. Lead optimization of this series led to the discovery of TAK-733. This was advanced to Phase I clinical studies for cancer treatment. © 2011 Published by Elsevier Ltd.

Jiangsu Hengrui Medicine Co. and Shanghai Hengrui Pharmaceuticals Co. | Date: 2012-12-27

Disclosed in the present invention are polycyclic derivatives as represented by general formula (I), the preparation method thereof, pharmaceutical compositions containing the derivatives and uses thereof as therapeutic agents, especially the GPR40 agonist and in preparation of drugs for treating diseases such as diabetes and metabolic disorders, etc., wherein each substituent in the general formula (I) has the same definition as in the description.

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