Identification of a Potent and Selective Free Fatty Acid Receptor 1 (FFA1/GPR40) Agonist with Favorable Physicochemical and in Vitro ADME Properties

被引：60

作者：

Christiansen, Elisabeth ^{[1
]}

Urban, Christian ^{[2
]}

Grundmann, Manuel ^{[3
]}

Due-Hansen, Maria E. ^{[1
]}

Hagesaether, Ellen ^{[1
]}

Schmidt, Johannes ^{[3
]}

Pardo, Leonardo ^{[4
]}

Ullrich, Susanne ^{[5
]}

Kostenis, Evi ^{[3
]}

Kassack, Matthias ^{[2
]}

Ulven, Trond ^{[1
]}

机构：

[1] Univ So Denmark, Dept Chem & Phys, DK-5230 Odense M, Denmark

[2] Univ Dusseldorf, Inst Pharmaceut & Med Chem, D-40225 Dusseldorf, Germany

[3] Univ Bonn, Inst Pharmaceut Biol, D-53115 Bonn, Germany

[4] Univ Autonoma Barcelona, Fac Med, Unitat Bioestat, Lab Med Computac, E-08193 Barcelona, Spain

[5] Univ Tubingen, Div Endocrinol Diabetol & Clin Chem, Dept Internal Med, D-72076 Tubingen, Germany

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2011年 / 54卷 / 19期

关键词：

PROTEIN-COUPLED RECEPTOR; PANCREATIC BETA-CELLS; INSULIN-SECRETION; SMALL-MOLECULE; DRUG DISCOVERY; GPR40; AGONIST; ANTAGONISTS; GLUCOSE; MICE; STIMULATION;

D O I：

10.1021/jm2005699

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The free fatty acid receptor 1 (FFA1, also known as GPR40) enhances glucose-stimulated insulin secretion from pancreatic beta-cells and is recognized as an interesting new target for treatment of type 2 diabetes. Several series of selective FFA1 agonists are already known. Most of these are derived from free fatty acids (FFAs) or glitazones and are relatively lipophilic. Aiming for the development of potent, selective, and less lipophilic FFA1 agonists, the terminal phenyl of a known compound series was replaced by nitrogen containing heterocycles. This resulted in the identification of 37, a selective FFA1 agonist with potent activity on recombinant human FFA1 receptors and on the rat insulinoma cell line INS-1E, optimal lipophilicity, and excellent in vitro permeability and metabolic stability.

引用

页码：6691 / 6703

页数：13

共 51 条

[1] Deletion of GPR40 Impairs Glucose-Induced Insulin Secretion In Vivo in Mice Without Affecting Intracellular Fuel Metabolism in Islets [J].

Alquier, Thierry ;

Peyot, Marie-Line ;

Latour, Martin G. ;

Kebede, Melkam ;

Sorensen, Christina M. ;

Gesta, Stephane ;

Kahn, C. Ronald ;

Smith, Richard D. ;

Jetton, Thomas L. ;

Metz, Thomas O. ;

Prentki, Marc ;

Poitout, Vincent .

DIABETES, 2009, 58 (11) :2607-2615

[2]

[Anonymous], PYMOL MOL GRAPH SYST

[3]

Ballesteros J. A., 1995, Neuroscience Methods, V25, P366, DOI [10.1016/S1043-9471(05)80049-7, DOI 10.1016/S1043-9471(05)80049-7, DOI 10.1016/S1043-9471]

[4] Progress in the discovery and development of small-molecule modulators of G-protein-coupled receptor 40 (GPR40/FFA1/FFAR1): an emerging target for type 2 diabetes [J].

Bharate, Sandip B. ;

Nemmani, Kumar V. S. ;

Vishwakarma, Ram A. .

EXPERT OPINION ON THERAPEUTIC PATENTS, 2009, 19 (02) :237-264

[5] Pharmacological regulation of insulin secretion in MIN6 cells through the fatty acid receptor GPR40: identification of agonist and antagonist small molecules [J].

Briscoe, Celia P. ;

Peat, Andrew J. ;

McKeown, Stephen C. ;

Corbett, David F. ;

Goetz, Aaron S. ;

Littleton, Thomas R. ;

McCoy, David C. ;

Kenakin, Terry P. ;

Andrews, John L. ;

Ammala, Carina ;

Fornwald, James A. ;

Ignar, Diane M. ;

Jenkinson, Stephen .

BRITISH JOURNAL OF PHARMACOLOGY, 2006, 148 (05) :619-628

[6] 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

[7]

Case D.A., 2006, AMBER 9

[8] High-resolution crystal structure of an engineered human β2-adrenergic G protein-coupled receptor [J].

Cherezov, Vadim ;

Rosenbaum, Daniel M. ;

Hanson, Michael A. ;

Rasmussen, Soren G. F. ;

Thian, Foon Sun ;

Kobilka, Tong Sun ;

Choi, Hee-Jung ;

Kuhn, Peter ;

Weis, William I. ;

Kobilka, Brian K. ;

Stevens, Raymond C. .

SCIENCE, 2007, 318 (5854) :1258-1265

[9] Discovery of Potent and Selective Agonists for the Free Fatty Acid Receptor 1 (FFA1/GPR40), a Potential Target for the Treatment of Type II Diabetes [J].

Christiansen, Elisabeth ;

Urban, Christian ;

Merten, Nicole ;

Liebscher, Kathrin ;

Karlsen, Kasper K. ;

Hamacher, Alexandra ;

Spinrath, Andreas ;

Bond, Andrew D. ;

Drewke, Christel ;

Ullrich, Susanne ;

Kassack, Matthias U. ;

Kostenis, Evi ;

Ulven, Trond .

JOURNAL OF MEDICINAL CHEMISTRY, 2008, 51 (22) :7061-7064

[10] Structure-Activity Study of Dihydrocinnamic Acids and Discovery of the Potent FFA1 (GPR40) Agonist TUG-469 [J].

Christiansen, Elisabeth ;

Due-Hansen, Maria E. ;

Urban, Christian ;

Merten, Nicole ;

Pfleiderer, Michael ;

Karlsen, Kasper K. ;

Rasmussen, Sanne S. ;

Steensgaard, Mette ;

Hamacher, Alexandra ;

Schmidt, Johannes ;

Drewke, Christel ;

Petersen, Rasmus Koefoed ;

Kristiansen, Karsten ;

Ullrich, Susanne ;

Kostenis, Evi ;

Kassack, Matthias U. ;

Ulven, Trond .

ACS MEDICINAL CHEMISTRY LETTERS, 2010, 1 (07) :345-349

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