Wuxi PharmaTech Co.

Shanghai, China

Wuxi PharmaTech Co.

Shanghai, China
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Boga S.B.,Merck And Co. | Alhassan A.-B.,Merck And Co. | Liu J.,Merck And Co. | Guiadeen D.,Merck And Co. | And 27 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2017

8-Amino-imidazo[1,5-a]pyrazine-based Bruton's tyrosine kinase (BTK) inhibitors, such as 6, exhibited potent inhibition of BTK but required improvements in both kinase and hERG selectivity (Liu et al., 2016; Gao et al., 2017). In an effort to maintain the inhibitory activity of these analogs and improve their selectivity profiles, we carried out SAR exploration of groups at the 3-position of pyrazine compound 6. This effort led to the discovery of the morpholine group as an optimized pharmacophore. Compounds 13, 23 and 38 displayed excellent BTK potencies, kinase and hERG selectivities, and pharmacokinetic profiles. © 2017 Elsevier Ltd


Chen S.-Q.,Hangzhou Normal University | Zhang Y.-C.,WuXi PharmaTech Co. | Liu F.-M.,Hangzhou Normal University | Liu F.-M.,Xinjiang University
Journal of Chemical Crystallography | Year: 2011

The crystal structure of the product (Z)-2-((Z)-((Z)-1,3-diphenyl-2-(1H-1, 2,4-triazol-1-yl)allylidene)amino) phenyl N-hydroxybenzimidothioate (4) was obtained by single crystal X-ray diffraction. The title compound, C 30H23N5OS (4), crystallizes in the triclinic space group, P-1, with unit cell parameters a = 8.3306(17) Å, b = 11.394(2) Å, c = 14.560(3) Å, α = 78.75(3)8, β = 89.96(3)8, γ = 70.56(3)8, Z = 2. In the crystal structure, adjacent molecules are linked by O-H N hydrogen bonds. H-bonds and p-p stacking are the main non-bonding interactions in the molecular structure and give support to molecular packing stability. In addition, the structure is supported by a weak intermolecular C-H Cg π-ring interaction. Detail of the synthesis, structures, and spectroscopic properties of the title compound is discussed. © Springer Science+Business Media, LLC 2010.


Gao X.,MRL | Wang J.,MRL | Liu J.,MRL | Guiadeen D.,MRL | And 29 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2017

We report the design and synthesis of a series of novel Bruton's Tyrosine Kinase (BTK) inhibitors with a carboxylic acid moiety in the ribose pocket. This series of compounds has demonstrated much improved off-target selectivities including adenosine uptake (AdU) inhibition compared to the piperidine amide series. Optimization of the initial lead compound 4 based on BTK enzyme inhibition, and human peripheral blood mononuclear cell (hPBMC) and human whole blood (hWB) activity led to the discovery of compound 40, with potent BTK inhibition, reduced off target activities, as well as favorable pharmacokinetic profile in both rat and dog. © 2016 Elsevier Ltd


Lemaire S.,Johnson and Johnson Pharmaceutical Development | Houpis I.,Johnson and Johnson Pharmaceutical Development | Wechselberger R.,Johnson and Johnson Pharmaceutical Development | Langens J.,Johnson and Johnson Pharmaceutical Development | And 12 more authors.
Journal of Organic Chemistry | Year: 2011

Diastereoselective hydrogenation of 2′-deoxy-2′-exo- methyleneuridine was carried out under homogeneous conditions using a low loading of a chiral Rh catalyst. This, coupled with improvements in the synthesis of the substrate, allowed the smooth pilot plant preparation of the title compound on >10 kg scale. © 2010 American Chemical Society.


Liu B.,Jinan University | Zhang T.,Jinan University | Zhang T.,Wuxi PharmaTech Co. | Zhang X.,Jinan University | And 2 more authors.
Zhongguo Zhongyao Zazhi | Year: 2010

Objective: To study the chemical constituents of Laggera pterodonta. Method: The ethanol extract of L. pterodonta was isolated by column chromatogramphy on silica gel, ODS, and Sephadex LH-20 to afford compounds. The structures of the obtained compounds were identified by chemical reactions and spectroscopic analysis. Result: Nineteen compounds were separated and identified to be pterodondiol (1), ilicic acid (2), artemitin (3), chrysosplenetin B(4), 3,5-dihydroxy-3′,4′,6,7-tetramethoxyflavone (5), chrysosplenol D (6), 5,6,4′-trihydroxy-3,7-dimethoxyflavone (7), quercetin (8), tamarixetin (9), patuletin (10), quercetin-3-O-β-D-galactopyranoside (11), patuletin-3-O-β-D-glucopyranoside (12), helichrysoside (13), 4,5,7-trihydroxy-6-methoxyflavone-3-O-β-D-rutinoside (14), kaempferol-3-O-β-D-glucopyranoside (15), stigmasterol (16), stigmasterol 3-O-β-D-glucopyranoside (17), 2-hydroxy-benzoic acid (18), β-sitosterol (19). Conclusion: Compounds 5, 7, 9-15, and 17-18 were isolated from this plant for the first time. The 13C-NMR data of compound 7 is reported for the first time.


Liu J.,Merck And Co. | Guiadeen D.,Merck And Co. | Krikorian A.,Merck And Co. | Gao X.,Merck And Co. | And 30 more authors.
ACS Medicinal Chemistry Letters | Year: 2016

Bruton's tyrosine kinase (BTK) is a Tec family kinase with a well-defined role in the B cell receptor (BCR) pathway. It has become an attractive kinase target for selective B cell inhibition and for the treatment of B cell related diseases. We report a series of compounds based on 8-amino-imidazo[1,5-a]pyrazine that are potent reversible BTK inhibitors with excellent kinase selectivity. Selectivity is achieved through specific interactions of the ligand with the kinase hinge and driven by aminopyridine hydrogen bondings with Ser538 and Asp539, and by hydrophobic interaction of trifluoropyridine in the back pocket. These interactions are evident in the X-ray crystal structure of the lead compounds 1 and 3 in the complex with the BTK enzyme. Our lead compounds show desirable PK profiles and efficacy in the preclinical rat collagen induced arthritis model. © 2015 American Chemical Society.


Chen S.-Q.,Hangzhou Normal University | Zhang Y.-C.,WuXi PharmaTech. Co. | Liu F.-M.,Hangzhou Normal University
Phosphorus, Sulfur and Silicon and the Related Elements | Year: 2011

Chemical Equation Presented In this study, several new 1-(4-aryl-5- triazolyl-2-thiazolyl)-3,5-diaryl-2-pyrazolines (3a-r) were synthesized by reacting 3,5-diaryl1-thiocarbamoyl-2-pyrazolines (1) with 2-bromo-1-aryl-2-(1H- 1,2,4-triazol-1-yl) ethanones (2) in boiling ethanol. The chemical structures of the compounds were verified by IR, 1H NMR, ESI-MS spectroscopic data, and elemental analyses. Copyright © Taylor & Francis Group, LLC.


Wang N.-Y.,University of Sichuan | Zuo W.-Q.,University of Sichuan | Xu Y.,University of Sichuan | Gao C.,University of Sichuan | And 8 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2014

Current treatment for hepatitis C is barely satisfactory, there is an urgent need to develop novel agents for combating hepatitis C virus infection. This study discovered a new class of thieno[2,3-b]pyridine derivatives as HCV inhibitors. First, a hit compound characterized by a thienopyridine core was identified in a cell-based screening of our privileged small molecule library. And then, structure activity relationship study of the hit compound led to the discovery of several potent compounds without obvious cytotoxicity in vitro (12c, EC50 = 3.3 μM, SI >30.3, 12b, EC50 = 3.5 μM, SI >28.6, 10l, EC50 = 3.9 μM, SI >25.6, 12o, EC 50 = 4.5 μM, SI >22.2, respectively). Although the mechanism of them had not been clearly elucidated, our preliminary optimization of this class of compounds had provided us a start point to develop new anti-HCV agents. © 2014 Elsevier Ltd. All rights reserved.


PubMed | University of Sichuan, WuXi PharmaTech Co. and China Pharmaceutical University
Type: Journal Article | Journal: Bioorganic & medicinal chemistry letters | Year: 2014

Current treatment for hepatitis C is barely satisfactory, there is an urgent need to develop novel agents for combating hepatitis C virus infection. This study discovered a new class of thieno[2,3-b]pyridine derivatives as HCV inhibitors. First, a hit compound characterized by a thienopyridine core was identified in a cell-based screening of our privileged small molecule library. And then, structure activity relationship study of the hit compound led to the discovery of several potent compounds without obvious cytotoxicity in vitro (12c, EC50=3.3M, SI >30.3, 12b, EC50=3.5M, SI >28.6, 10l, EC50=3.9M, SI >25.6, 12o, EC50=4.5M, SI >22.2, respectively). Although the mechanism of them had not been clearly elucidated, our preliminary optimization of this class of compounds had provided us a start point to develop new anti-HCV agents.


PubMed | Merck And Co. and WuXi PharmaTech Co.
Type: Journal Article | Journal: ACS medicinal chemistry letters | Year: 2016

Brutons tyrosine kinase (BTK) is a Tec family kinase with a well-defined role in the B cell receptor (BCR) pathway. It has become an attractive kinase target for selective B cell inhibition and for the treatment of B cell related diseases. We report a series of compounds based on 8-amino-imidazo[1,5-a]pyrazine that are potent reversible BTK inhibitors with excellent kinase selectivity. Selectivity is achieved through specific interactions of the ligand with the kinase hinge and driven by aminopyridine hydrogen bondings with Ser538 and Asp539, and by hydrophobic interaction of trifluoropyridine in the back pocket. These interactions are evident in the X-ray crystal structure of the lead compounds 1 and 3 in the complex with the BTK enzyme. Our lead compounds show desirable PK profiles and efficacy in the preclinical rat collagen induced arthritis model.

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