Discovery of fused bicyclic agonists of the orphan G-protein coupled receptor GPR119 with in vivo activity in rodent models of glucose control

被引：58

作者：

Semple, Graeme ^{[1
]}

Ren, Albert ^{[1
]}

Fioravanti, Beatriz ^{[1
]}

Pereira, Guillherme ^{[1
]}

Calderon, Imelda ^{[1
]}

Choi, Karoline ^{[1
]}

Xiong, Yifeng ^{[1
]}

Shin, Young-Jun ^{[1
]}

Gharbaoui, Tawfik ^{[1
]}

Sage, Carleton R. ^{[1
]}

Morgan, Michael ^{[2
]}

Xing, Charles ^{[3
]}

Chu, Zhi-Liang ^{[3
]}

Leonard, James N. ^{[3
]}

Grottick, Andrew J. ^{[3
]}

Al-Shamma, Hussein ^{[3
]}

Liang, Yin ^{[4
]}

Demarest, Keith T. ^{[4
]}

Jones, Robert M. ^{[1
]}

机构：

[1] Arena Pharmaceut, Med Chem, San Diego, CA 92121 USA

[2] Arena Pharmaceut, DMPK, San Diego, CA 92121 USA

[3] Arena Pharmaceut, Discovery Biol, San Diego, CA 92121 USA

[4] Johnson & Johnson Pharmaceut Res & Dev LLC, Spring House, PA 19477 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2011年 / 21卷 / 10期

关键词：

GPR119; agonists; GPCR; Diabetes; GDIS; GLYCEMIC CONTROL; G-PROTEIN-COUPLED-RECEPTOR-119; OLEOYLETHANOLAMIDE; ACTIVATION; RELEASE;

D O I：

10.1016/j.bmcl.2011.03.007

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We herein outline the design of a new series of agonists of the pancreatic and GI-expressed orphan G-protein coupled receptor GPR119, a target that has been of significant recent interest in the field of metabolism, starting from our prototypical agonist AR231453. A number of key parameters were improved first by incorporation of a pyrazolopyrimidine core to create a new structural series and secondly by the introduction of a piperidine ether group capped with a carbamate. Chronic treatment with one compound from the series, 3k, showed for the first time that blood glucose and glycated hemoglobin (HbA1c) levels could be significantly reduced in Zucker Diabetic Fatty (ZDF) rats over several weeks of dosing. As a result of these and other data described here, 3k (APD668, JNJ-28630368) was the first compound with this mechanism of action to be progressed into clinical development for the treatment of diabetes. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：3134 / 3141

页数：8

共 25 条

[1] Discovery of a second generation agonist of the orphan G-protein coupled receptor GPR119 with an improved profile
Semple, Graeme
Lehmann, Juerg
Wong, Amy
Ren, Albert
Bruce, Marc
Shin, Young-Jun
Sage, Carleton R.
Morgan, Michael
Chen, Wei-Chao
Sebring, Kristen
Chu, Zhi-Liang
Leonard, James N.
Al-Shamma, Hussein
Grottick, Andrew J.
Du, Fuyong
Liang, Yin
Demarest, Keith
Jones, Robert M.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2012, 22 (04) : 1750 - 1755
[2] Circumventing Seizure Activity in a Series of G Protein Coupled Receptor 119 (GPR119) Agonists
Scott, James S.
Bowker, Suzanne S.
Brocklehurst, Katy J.
Brown, Hayley S.
Clarke, David S.
Easter, Alison
Ertan, Anne
Goldberg, Kristin
Hudson, Julian A.
Kavanagh, Stefan
Laber, David
Leach, Andrew G.
MacFaul, Philip A.
Martin, Elizabeth A.
McKerrecher, Darren
Schofield, Paul
Svensson, Per H.
Teague, Joanne
JOURNAL OF MEDICINAL CHEMISTRY, 2014, 57 (21) : 8984 - 8998
[3] Optimisation of aqueous solubility in a series of G protein coupled receptor 119 (GPR119) agonists
Scott, James S.
Birch, Alan M.
Brocklehurst, Katy J.
Brown, Hayley S.
Goldberg, Kristin
Groombridge, Sam D.
Hudson, Julian A.
Leach, Andrew G.
MacFaul, Philip A.
McKerrecher, Darren
Poultney, Ruth
Schofield, Paul
Svensson, Per H.
MEDCHEMCOMM, 2013, 4 (01) : 95 - 100
[4] G Protein-Coupled Receptor 119 (GPR119) Agonists for the Treatment of Diabetes: Recent Progress and Prevailing Challenges
Ritter, Kurt
Buning, Christian
Halland, Nis
Poverlein, Christoph
Schwink, Lothar
JOURNAL OF MEDICINAL CHEMISTRY, 2016, 59 (08) : 3579 - 3592
[5] GPR109a agonists. Part 2: Pyrazole-acids as agonists of the human orphan G-protein coupled receptor GPR109a
Imbriglio, Jason E.
Chang, Sookhee
Liang, Rui
Raghavan, Subharekha
Schmidt, Darby
Smenton, Abby
Tria, Scott
Schrader, Thomas O.
Jung, Jae-Kyu
Esser, Craig
Holt, Tom G.
Wolff, Michael S.
Taggart, Andrew K. P.
Cheng, Kang
Carballo-Jane, Ester
Waters, M. Gerard
Tata, James R.
Colletti, Steven L.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2010, 20 (15) : 4472 - 4474
[6] Discovery and characterization of novel small-molecule agonists of G protein-coupled receptor 119
Zhang, Shu-yong
Li, Jing
Xie, Xin
ACTA PHARMACOLOGICA SINICA, 2014, 35 (04) : 540 - 548
[7] Discovery and SAR of a Series of Agonists at Orphan G Protein-Coupled Receptor 139
Shi, Feng
Shen, Jing Kang
Chen, Danqi
Fog, Karina
Thirstrup, Kenneth
Hentzer, Morten
Karlsson, Jens-Jakob
Menon, Veena
Jones, Kenneth A.
Smith, Kelli E.
Smith, Garrick
ACS MEDICINAL CHEMISTRY LETTERS, 2011, 2 (04): : 303 - 306
[8] Discovery and characterization of novel smallmolecule agonists of G protein-coupled receptor 119
Shu-yong Zhang
Jing Li
Xin Xie
Acta Pharmacologica Sinica, 2014, 35 : 540 - 548
[9] GPR119, a novel G protein-coupled receptor target for the treatment of type 2 diabetes and obesity
Overton, H. A.
Fyfe, M. C. T.
Reynet, C.
BRITISH JOURNAL OF PHARMACOLOGY, 2008, 153 : S76 - S81
[10] Discovery and biological evaluation of novel G protein-coupled receptor 119 agonists for type 2 diabetes
Zhou, Ying
Wang, Youzhi
Zhang, Leilei
Tang, Chunlei
Feng, Bainian
ARCHIV DER PHARMAZIE, 2019, 352 (04)

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