药物化学实验室（张小虎 教授）

 张小虎，18新利体育 药学院教授，博士生导师

1990年毕业于北京大学化学系，获理学学士学位。1997年毕业于新泽西州立大学（Rutgers University-the State University of New Jersey），获博士学位。1998-2008年在美国圣地亚哥Strategene, an Agilent Company和Neurocrine Biosciences Inc.工作；2008-2011年在BioDuro, a PPD Company任职。历任研究员，资深研究员，项目经理，技术总监，资深总监，执行总监等。2012年4月加入18新利体育 药学院，任特聘教授，博士生导师。

张博士长期从事抗肿瘤药物和中枢神经系统药物的研究与开发，对以G蛋白偶联受体为靶点的小分子成药有丰富的经验和显著的成果。以腺苷受体A2A为靶点的抗帕金森综合症的研究得到了Michael Fox基金的资助，并成功开发出临床前候选化合物；以促肾上腺皮质激素释放因子受体CRF-R1为靶标的抗抑郁药物的研究最终使两个化合物进入一期和二期临床。张博士已发表学术论文40余篇，其中包括美国化学会志（Journal of the American Chemical Society），药物化学（Journal of Medicinal Chemistry）等刊物，所发表论文被广泛引用。张博士还是十几篇国际专利的发明者和合作发明者。

郑计岳，讲师

2005年毕业于兰州大学化学化工学院，获理学学士学位。2005-2010年在兰州大学厍学功教授课题组攻读博士学位，主要从事具有生理活性的天然产物全合成研究。毕业后加入上海睿智化学研究有限公司从事小分子药物的设计合成工作。2012年加入张小虎教授课题组。

主要研究方向

张博士课题组主要从事小分子药物的设计与合成研究，通过化合物筛选或结构设计得到先导化合物，进一步构效关系研究，优化其生理活性及成药性，开发出优秀的临床前候选化合物。

Ø 靶向中枢神经系统重大疾病的药物研发

以帕金森综合症、抑郁症、自闭症为靶向，寻找和发现新型小分子药物

Ø 新型抗肿瘤药物的研发

专注于胚胎通路（刺猬通路拮抗剂，豪猪蛋白拮抗剂等）以及肿瘤免疫治疗相关靶点的小分子药物研发

科研项目

1. 国家自然科学基金面上项目（81473090），刺猬通路拮抗剂作为抗肿瘤药物的研发。2015-2018，主持，在研。

2. 国家自然科学基金面上项目（81273372），腺苷受体A2A拮抗剂作为治疗帕金森综合症新型药物的可行性研究。2013-2016，主持，已完成。

代表性著作

[1] Identification of a New Series of Potent Adenosine A_2A Receptor Antagonists Based on 4-Amino-5-carbonitrile Pyrimidine Template for the Treatment of Parkinson's Disease. Yang, Z; Li, L; Zheng, J; Ma, H; Tian, S; Li, J; Zhang, H; Zhen, X;* Zhang, X.* ACS Chem. Neurosci. 2016, 7, 1575-1584.

[2] Design, synthesis, and evaluation of novel porcupine inhibitors featuring a fused 3-ring system based on the 'reversed' amide scaffold. Xu, Z; Xu, X; O'Laoi, R; Ma, H; Zheng, J;* Chen, S; Luo, L;* Hu, Z; He, S; Li, J; Zhang, H; Zhang, X.* Bioorg. Med. Chem. 2016, 24, 5861-5872.

[3] Design, synthesis, and evaluation of potent Wnt signaling inhibitors featuring a fused 3-ring system. Xu, Z.; Li, J.; Wu, Y.; Sun, Z.; Luo, L.*; Hu, Z.; He, S.; Zheng, J.*; Zhang, H.; Zhang, X.* Eur. J. Med. Chem. 2016, 108, 154-165.

[4] Exploration of the linkage elements of porcupine antagonists led to potent Wnt signaling pathway inhibitors. Dong, Y.; Li, K.; Xu, Z.; Ma, H.; Zheng, J.; Hu, Z.; He, S.; Wu, Y.; Sun, Z.; Luo, L.*; Li, J.; Zhang, H.; Zhang, X.* Bioorg. Med. Chem. 2015, 23, 6855-6868.

[5] Discovery of a 6-(pyridin-3-yl)benzo[d]thiazole template for optimization of hedgehog and PI3K/AKT/mTOR dual inhibitors. Yang, Z.; Ma, H.; Sun, Z.; Luo, L.*; Tian, S.; Zheng, J.; Zhang, X.* Bioorg. Med. Chem. Lett. 2015, 25, 3665-3670.

[6] Design, synthesis, and structure-activity-relationship of tetrahydrothiazolopyridine derivatives as potent smoothened antagonists. Ma, H.; Lu, W.; Sun, Z.; Luo, L.*; Geng, D.; Yang, Z.; Li, E.; Zheng, J.; Wang, M.; Zhang, H.; Yang, S.; Zhang, X.* Eur. J. Med. Chem. 2015, 89, 721-732.

[7] Scaffold hopping approach to a new series of smoothened antagonists. Lu, W.; Geng, D.; Sun, Z.; Yang, Z.; Ma, H.; Zheng, J.; Zhang, X.* Bioorg. Med. Chem. Lett. 2014, 24, 2300-2304.

[8] Optimization of 6-Heterocyclic-2-(1H-pyrazol-1-yl)-N-(pyridin-2-yl) pyrimidin-4-amine as Potent Adenosine A(2A) Receptor Antagonists for the Treatment of Parkinson's Disease. Zheng, J.; Yang, Z.; Li, X.; Li, L.; Ma, H.; Wang, M.; Zhang, H.; Zhen, X.*; Zhang, X.* ACS Chem. Neurosci. 2014, 5, 674-682.

[9] Replacement of amide with bioisosteres led to a new series of potent adenosine A_2A receptor antagonists. Yang, Z.; Li, X.; Ma, H.; Zheng, J.; Zhen, X.; Zhang, X.* Bioorg. Med. Chem. Lett. 2014, 24, 152-155.

[10] Padilla, F.; Bhagirath, N.; Chen, S.; Chiao, E.; Goldstein, D.M.; Hermann, J.C.; Hsu, J.; Kennedy-Smith, J.J.; Kuglstatter, A.; Liao, C.; Liu, W.; Lowrie, Jr. L.E.; Luk , K.;  Lynch, S.M.; Menke, J.; Niu, L.; Owens, T.D.; O-Yang, C.; Railkar, A.; Schoenfeld, R.C.; Slade, M.; Steiner, S.; Tan, Y-C.; Villasenor, A.G.; Wang, C.; Wanner, J.; Xie, W.W.; Xu, D.; Zhang, X.; Zhou, M.; Lucas, M.C. Pyrrolopyrazines as selective spleen tyrosine kinase inhibitors. J. Med. Chem. 2013, 56, 1677-1692.

[11] Lucas, M.C.; Goldstein, D.M.; Hermann, J.C.; Kuglstatter, A.; Liu, W.; Luk, K.C.; Padilla, F.; Slade, M.; Wanner, J.; Xie, W.W.; Zhang, X.; Liao, C. Rational design of highly selective spleen tyrosine kinase inhibitors. J. Med. Chem. 2012, 55, 10414-10423.

[12] Tellow, J.; Lanier-Gross, M.; Moorjani, M.; Lin, E.; Luo, Z.; Slee, D.; Zhang, X.; Hoare, S.; Grigoriadis, D.; Denis, Y.; Di Fabio, R.; Modugno, E.; Saunders, J.; Williams, J. Discovery of NBI-77860/GSK561679, a potent Corticotropin Releasing Factor (CRF1) Receptor Antagonist with Improved Pharmacokinetic Properties. Bioorg. Med. Chem. Lett. 2010, 20, 7259-7264. 

[13] Cai, H.; Chavez, F.; Dunford, P.J.; Greenspan, A.J.; Meduna, S.P.; Quiroz, J.A.; Savall, B.M.; Tays, K.L.; Thurmond, R.L.; Wei, J.; Wolin, R.L.; Zhang, X. (with J&J) Preparation of aminopyridazine derivatives and analogs for use as histamine H₄ receptor modulators. World Patent, WO2009152325, 2009.

[14] Lanier, M.; Luo, Z.; Chen, Y.; Lin, E.; Moorjani, M.; Slee, D.; Tellew, J.; Zhang, X.; Lechner, S.; Markison, S.; Joswig., Kargo, W.; Piercey, J.; Santos, M.; Malany, S.; Gross R.; Williams, J.; Castro-Palomino, J.; Crespo, M.; Prat, M.; Gual, S.; Diaz, J.; Wen, J.; O’Brien, Z.; Saunders, J. Report of 2-Amino-N-Pyrimidin-4-yl Acetamides as A_2A Receptor Antagonists with Improved Drug Like Properties and In Vivo Efficacy. J. Med.Chem. 2009, 52, 709-717.

[15] Zhang, X.; Tellew, J.; Luo, Z.; Moorjani, M.; Lin, E.; Lanier, M.; Chen, Y.; Williams, J.; Saunders, J.; Lechner, S.; Markison, S.; Joswig, T.; Malany, S.; Santos, M.; Gross R.; Wen, J.; O’Brien, Z.; Slee, D.Lead Optimization of 4-Acetylamino-2-(3, 5-dimethylpyrazol-1-yl)-6-pyridylpyrimidines as Adenosine A_2A Antagonists for the Treatment of Parkinson’s Disease. J. Med. Chem. 2008, 51, 7099-7110.

[16] Slee, D.; Zhang, X.; Moorjani, M.; Lin, E.; Lanier, M.; Chen, Y.; Rueter, J.; Lechner, S.; Markison, S.; Malany, S.; Joswig, T.; Santos, M.; Gross R.; Williams, J.; Castro-Palomino, J.; Crespo, M.; Prat, M.; Gual, S.; Diaz, J.; Wen, J.; O’Brien, Z.; Saunders, J. Identification of Novel, Water Soluble, 2-Amino-N-Pyrimidin-4-yl Acetamides as A_2A Receptor Antagonists with In Vivo Efficacy. J.Med. Chem. 2008, 51, 400-406.

[17] Slee, D.; Chen, Y.; Zhang, X.; Moorjani, M.; Lanier, M.; Lin, E.; Rueter, J.; Williams, J.; Lechner, S.; Markison, S.; Malany, S.; Santos, M.; Gross R.; Jalali, K.; Sai, Y.; Zou, Z.; Yang, C.; Castro-Palomino, J.; Crespo, M.; Prat, M.; Gual, S.; Diaz, J.; Wen, J.; Saunders, J. 2-Amino-N-Pyrimidin-4-yl Acetamides as A_2A Receptor Antagonists: Part 1: SAR and Optimization of Heterocyclic Substituents. J. Med. Chem. 2008, 51, 1719-1729.

[18] Slee, D.; Moorjani, M.; Zhang, X.; Lin, E.; Lanier, M.; Chen, Y.; Rueter, J.; Lechner, S.; Markison, S.; Malany, S.; Joswig., T.; Santos, M.; Gross R.; Williams, J.; Castro-Palomino, J.; Crespo, M.; Prat, M.; Gual, S.; Diaz, J.; Jalali, K.; Sai, Y.; Zou, Z.; Yang, C.; Wen, J.; O’Brien, Z.; Petroski, R.; Saunders, J. 2-Amino-N-Pyrimidin-4-yl Acetamides as A_2A Receptor Antagonists: Part 2: Reduction of hERG Activity, Observed Species Selectivity and SAR. J. Med. Chem. 2008, 51, 1730-1739.

[19] Zhang, X.; Rueter, J.; Chen, Y.; Moorjani, M.; Lanier, M.; Lin, E.; Gross R.; Tellew, J.; Williams, J.; Lechner, S.; Markison, S.; Joswig, T.; Malany, S.; Santos, M.; Castro-Palomino, J.; Crespo, M.; Prat, M.; Gual, S.; Diaz, J.; Saunders, J.; Slee, D. Synthesis of N-Pyrimidinyl-2-Phenoxyacetamides as Adenosine A_2A Receptor Antagonists. Bioorg. Med. Chem. Lett. 2008, 18, 1778-1783.

[20] Moorjani, M.; Zhang, X.; Chen, Y.; Lin, E.; Rueter, J.; Gross, R.; Lanier, M.; Tellew., J.; Williams, J.; Lechner, S.; Markison, S.; Malany, S.; Santos, M.; Ekhlassi, P.; Castro-Palomino, J.; Crespo, M.; Prat, M.; Gual, S.; Diaz, J.; Saunders, J.; Slee, D. 2, 6-Diaryl-4-Phenacylaminopyrimidines as Potent and Selective Adenosine A_2A Antagonists with Reduced hERG Liability. Bioor. Med. Chem. Lett. 2008, 18, 1269-1273.

[21] Moorjani, M.; Lou, Z.; Lin, E.; Vong, B.; Chen, Y.; Zhang, X.; Rueter, J.; Gross, R.; Lanier, M.; Tellew, J.; Williams, J.; Lechner, S.; Malany, S.; Santos, M.; Crespo, M.; Diaz, J.; Saunders, J.; Slee, D. 2, 6-Diaryl-4-acylaminopyrimidines as Potent and Selective Adenosine A_2A Antagonist with Improved Solubility and Metabolic Stability. Bioorg. Med.Chem. Lett. 2008, 18, 5402-5405.

[22] Zhang, X.; Gaffney, B.; Jones, R. A. ¹⁵N NMR of Two Specifically Labeled RNA Fragments Containing Tandem GA Pairs. J. Am. Chem. Soc. 1998, 120, 6625-6626.

[23] Zhang, X.; Gaffney, B.; Jones, R. A. ¹⁵N NMR of a Specifically Labeled RNA Fragments Containing GU Pairs. Zhang, X.; Gaffney, B.; Jones, R. A. J. Am. Chem. Soc. 1998, 120, 615-618.

[24] Zhang, X.; Gaffney, B.; Jones, R. A. ¹⁵N NMR of a Specifically Labeled RNA Fragment Containing Intrahelical GU Wobble Pairs. J. Am. Chem. Soc. 1997, 119, 6432-6433.