Discovery of Chromane Propionic Acid Analogues as Selective Agonists of GPR120 with in Vivo Activity in Rodents

被引：29

作者：

Adams, Gregory L. ^{[2
]}

Velazquez, Francisco ^{[1
]}

Jayne, Charles ^{[1
]}

Shah, Unmesh ^{[1
,4
]}

Miao, Shouwu ^{[1
]}

Ashley, Eric R. ^{[1
]}

Madeira, Maria ^{[1
]}

Akiyama, Taro E. ^{[1
]}

Di Salvo, Jerry ^{[1
]}

Suzuki, Takao ^{[3
]}

Wang, Nengxue ^{[3
]}

Quang Truong ^{[1
]}

Gilbert, Eric ^{[1
]}

Zhou, Dan ^{[1
]}

Verras, Andreas ^{[1
]}

Kirkland, Melissa ^{[1
,5
]}

Pachanski, Michele ^{[1
]}

Powles, Maryann ^{[1
]}

Yin, Wu ^{[1
]}

Ujjainwalla, Feroze ^{[1
]}

Venkatraman, Srikanth ^{[1
]}

Edmondson, Scott D. ^{[1
]}

机构：

[1] Merck & Co Inc, Kenilworth, NJ 07033 USA

[2] Merck & Co Inc, West Point, PA 19486 USA

[3] WuXi AppTec, Shanghai 200131, Peoples R China

[4] Jones Day, 250 Vesey St, New York, NY 10281 USA

[5] Charles River Labs, 334 South St, Shrewsbury, MA 01545 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2017年 / 8卷 / 01期

关键词：

GPR120; FFAR4; insulin sensitization; type; 2; diabetes; chromane; INSULIN-RESISTANCE; RECEPTOR GPR120; INHIBITION; SECRETION; BINDING; LIFE; HIT;

D O I：

10.1021/acsmedchemlett.6b00394

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

GPR120 (FFAR4) is a fatty acid sensing G protein coupled receptor (GPCR) that has been identified as a target for possible treatment of type 2 diabetes. A selective activator of GPR120 containing a chromane scaffold has been designed, synthesized, and evaluated in vivo. Results of these efforts suggest that chromane propionic acid 18 is a suitable tool molecule for further animal studies. Compound 18 is selective over the closely related target GPR40 (FFAR1), has a clean off-target profile, demonstrates suitable pharmacokinetic properties, and has been evaluated in wild-type/knockout GPR120 mouse oGTT studies.

引用

页码：96 / 101

页数：6

共 30 条

[1]

Amos AF, 1997, DIABETIC MED, V14, pS7, DOI 10.1002/(SICI)1096-9136(199712)14:5+<S7::AID-DIA522>3.3.CO

[2]

2-I

[3]

[Anonymous], 2013, IDF DIABETES ATLAS

[4] Non-Acidic Free Fatty Acid Receptor 4 Agonists with Antidiabetic Activity [J].

Azevedo, Carlos M. G. ;

Watterson, Kenneth R. ;

Wargent, Ed T. ;

Hansen, Steffen V. F. ;

Hudson, Brian D. ;

Kepczynska, Malgorzata A. ;

Dunlop, Julia ;

Shimpukade, Bharat ;

Christiansen, Elisabeth ;

Milligan, Graeme ;

Stocker, Claire J. ;

Ulven, Trond .

JOURNAL OF MEDICINAL CHEMISTRY, 2016, 59 (19) :8868-8878

[5] Beyond PPARs and Metformin: New Insulin Sensitizers for the Treatment of Type 2 Diabetes [J].

Carpino, Philip A. ;

Hepworth, David .

ANNUAL REPORTS IN MEDICINAL CHEMISTRY, VOL 47, 2012, 47 :177-192

[6] From ionic currents to molecular mechanisms: The structure and function of voltage-gated sodium channels [J].

Catterall, WA .

NEURON, 2000, 26 (01) :13-25

[7]

Chelliah M., PCT Int. Appl., Patent No. [WO2014059232A1, 2014059232]

[8]

Cox J. M., 2016, ACS MED CHEM LETT, DOI [10.1021/acsmedchem-lett.6600360, DOI 10.1021/ACSMEDCHEM-LETT.6600360]

[9] Type 2 diabetes as an inflammatory disease [J].

Donath, Marc Y. ;

Shoelson, Steven E. .

NATURE REVIEWS IMMUNOLOGY, 2011, 11 (02) :98-107

[10] Optimization of a tertiary alcohol series of phosphodiesterase-4 (PDE4) inhibitors:: Structure-activity relationship related to PDE4 inhibition and human ether-a-go-go related gene potassium channel binding affinity [J].

Friesen, RW ;

Ducharme, Y ;

Ball, RG ;

Blouin, M ;

Boulet, L ;

Côté, B ;

Frenette, R ;

Girard, M ;

Guay, D ;

Huang, Z ;

Jones, TR ;

Laliberté, F ;

Lynch, JJ ;

Mancini, J ;

Martins, E ;

Masson, P ;

Muise, E ;

Pon, DJ ;

Siegl, PKS ;

Styhler, A ;

Tsou, NN ;

Turner, MJ ;

Young, RN ;

Girard, Y .

JOURNAL OF MEDICINAL CHEMISTRY, 2003, 46 (12) :2413-2426

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