Design, synthesis and biological evaluation of a series of novel GPR40 agonists containing nitrogen heterocyclic rings

被引：10

作者：

Sun, Zhaozhu

Zhou, Tian

Pan, Xuan

Yang, Ying

Huan, Yi

Xiao, Zhiyan

Shen, Zhufang ^{[1
]}

Liu, Zhanzhu ^{[1
]}

机构：

[1] Peking Union Med Coll, Inst Materia Med, State Key Lab Bioact Subst & Funct Nat Med, Beijing 100050, Peoples R China

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2018年 / 28卷 / 18期

关键词：

Nitrogen-containing heterocycles; GPR40; agonists; Type; 2; diabetes; PANCREATIC BETA-CELLS; RECEPTOR; AGONISTS; INSULIN-SECRETION; FATTY-ACIDS; POTENT; DISCOVERY; SCAFFOLD;

D O I：

10.1016/j.bmcl.2018.07.048

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A novel series of GPR40 agonists is designed by introducing nitrogen-containing heterocyclic ring at the terminal phenyl ring of TAK-875 with the aim of decreasing its lipophilicity. Three different beta-substituted phenylpropionic acids were investigated as the acidic components. A total of 34 compounds have been synthesized, among which, compound 30 exhibited comparable GPR40 agonistic activity in vitro with TAK-875 and relatively lower lipophilicity through calculation (30, EC50 = 1.2 mu M, cLogP = 1.3; TAK-875: EC50 = 5.1 mu M, cLogP = 3.4). Moreover, compound 30 was able to enhance the insulin secretion of primary islets isolated from normal ICR mice and showed no obvious inhibition against cytochromes P450 in vitro. In vivo, compound 30 exhibited efficacy in oral glucose tolerance test (oGTT) in normal ICR mice.

引用

页码：3050 / 3056

页数：7

共 20 条

[1] The orphan G protein-coupled receptor GPR40 is activated by medium and long chain fatty acids [J].

Briscoe, CP ;

Tadayyon, M ;

Andrews, JL ;

Benson, WG ;

Chambers, JK ;

Eilert, MM ;

Ellis, C ;

Elshourbagy, NA ;

Goetz, AS ;

Minnick, DT ;

Murdock, PR ;

Sauls, HR ;

Shabon, U ;

Spinage, LD ;

Strum, JC ;

Szekeres, PG ;

Tan, KB ;

Way, JM ;

Ignar, DM ;

Wilson, S ;

Muir, AI .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (13) :11303-11311

[2] Discovery of TUG-770: A Highly Potent Free Fatty Acid Receptor 1 (FFA1/GPR40) Agonist for Treatment of Type 2 Diabetes [J].

Christiansen, Elisabeth ;

Hansen, Steffen V. F. ;

Urban, Christian ;

Hudson, Brian D. ;

Wargent, Edward T. ;

Grundmann, Manuel ;

Jenkins, Laura ;

Zaibi, Mohamed ;

Stocker, Claire J. ;

Ullrich, Susanne ;

Kostenis, Evi ;

Kassack, Matthias U. ;

Milligan, Graeme ;

Cawthorne, Michael A. ;

Ulven, Trond .

ACS MEDICINAL CHEMISTRY LETTERS, 2013, 4 (05) :441-445

[3] Gpr40 is expressed in enteroendocrine cells and mediates free fatty acid stimulation of incretin secretion [J].

Edfalk, Sara ;

Steneberg, Par ;

Edlund, Helena .

DIABETES, 2008, 57 (09) :2280-2287

[4] The Discovery, Preclinical, and Early Clinical Development of Potent and Selective GPR40 Agonists for the Treatment of Type 2 Diabetes Mellitus (LY2881835, LY2922083, and LY2922470) [J].

Hamdouchi, Chafiq ;

Kahl, Steven D. ;

Lewis, Anjana Patel ;

Cardona, Guemalli R. ;

Zink, Richard W. ;

Chen, Keyue ;

Eessalu, Thomas E. ;

Ficorilli, James V. ;

Marcelo, Marialuisa C. ;

Otto, Keith A. ;

Wilbur, Kelly L. ;

Lineswala, Jayana P. ;

Piper, Jared L. ;

Coffey, D. Scott ;

Sweetana, Stephanie A. ;

Haas, Joseph V. ;

Brooks, Dawn A. ;

Pratt, Edward J. ;

Belin, Ruth M. ;

Deeg, Mark A. ;

Ma, Xiaosu ;

Cannady, Ellen A. ;

Johnson, Jason T. ;

Yumibe, Nathan P. ;

Chen, Qi ;

Maiti, Pranab ;

Montrose-Rafizadeh, Chahrzad ;

Chen, Yanyun ;

Miller, Anne Reifel .

JOURNAL OF MEDICINAL CHEMISTRY, 2016, 59 (24) :10891-10916

[5] AMG 837: A potent, orally bioavailable GPR40 agonist [J].

Houze, Jonathan B. ;

Zhu, Liusheng ;

Sun, Ying ;

Akerman, Michelle ;

Qiu, Wei ;

Zhang, Alex J. ;

Sharma, Rajiv ;

Schmitt, Michael ;

Wang, Yingcai ;

Liu, Jiwen ;

Liu, Jingian ;

Medina, Julio C. ;

Reagan, Jeff D. ;

Luo, Jian ;

Tonn, George ;

Zhang, Jane ;

Lu, Jenny Ying-Lin ;

Chen, Michael ;

Lopez, Edwin ;

Nguyen, Kathy ;

Yang, Li ;

Tang, Liang ;

Tian, Hui ;

Shuttleworth, Steven J. ;

Lin, Daniel C. -H. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2012, 22 (02) :1267-1270

[6] The dual DPP4 inhibitor and GPR119 agonist HBK001 regulates glycemic control and beta cell function ex and in vivo [J].

Huan, Yi ;

Jiang, Qian ;

Li, Gang ;

Bai, Guoliang ;

Zhou, Tian ;

Liu, Shuainan ;

Li, Caina ;

Liu, Quan ;

Sun, Sujuan ;

Yang, Miaomiao ;

Guo, Nan ;

Wang, Xing ;

Wang, Shusen ;

Liu, Yaojuan ;

Wang, Guanqiao ;

Huang, Haihong ;

Shen, Zhufang .

SCIENTIFIC REPORTS, 2017, 7

[7] Free fatty acids regulate insulin secretion from pancreatic β cells through GPR40 [J].

Itoh, Y ;

Kawamata, Y ;

Harada, M ;

Kobayashi, M ;

Fujii, R ;

Fukusumi, S ;

Ogi, K ;

Hosoya, M ;

Tanaka, Y ;

Uejima, H ;

Tanaka, H ;

Maruyama, M ;

Satoh, R ;

Okubo, S ;

Kizawa, H ;

Komatsu, H ;

Matsumura, F ;

Noguchi, Y ;

Shinobara, T ;

Hinuma, S ;

Fujisawa, Y ;

Fujino, M .

NATURE, 2003, 422 (6928) :173-176

[8] Petra, Osiris and Molinspiration (POM) together as a successful support in drug design: antibacterial activity and biopharmaceutical characterization of some azo Schiff bases [J].

Jarrahpour, Aliasghar ;

Fathi, Jihane ;

Mimouni, Mostafa ;

Ben Hadda, Taibi ;

Sheikh, Javed ;

Chohan, Zahid ;

Parvez, Ali .

MEDICINAL CHEMISTRY RESEARCH, 2012, 21 (08) :1984-1990

[9] Continued SAR exploration of 1,2,4-thiadiazole-containing scaffolds in the design of free fatty acid receptor 1 (GPR40) agonists [J].

Krasavin, Mikhail ;

Lukin, Alexei ;

Bakholdina, Anna ;

Zhurilo, Nikolay ;

Onopchenko, Oleksandra ;

Borysko, Petro ;

Zozulya, Sergey ;

Moore, Daniel ;

Tikhonova, Irina G. .

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2017, 140 :229-238

[10] Discovery of Potent and Orally Bioavailable GPR40 Full Agonists Bearing Thiophen-2-ylpropanoic Acid Scaffold [J].

Li, He ;

Huang, Qi ;

Chen, Cheng ;

Xu, Bin ;

Wang, He-Yao ;

Long, Ya-Qiu .

JOURNAL OF MEDICINAL CHEMISTRY, 2017, 60 (07) :2697-2717

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