Literature DB >> 24900707

Discovery and Optimization of Potent GPR40 Full Agonists Containing Tricyclic Spirocycles.

Yingcai Wang1, Jiwen Jim Liu1, Paul J Dransfield1, Liusheng Zhu1, Zhongyu Wang1, Xiaohui Du1, Xianyun Jiao1, Yongli Su1, An-Rong Li1, Sean P Brown1, Annie Kasparian1, Marc Vimolratana1, Ming Yu1, Vatee Pattaropong1, Jonathan B Houze1, Gayathri Swaminath1, Thanhvien Tran1, Khanh Nguyen1, Qi Guo1, Jane Zhang1, Run Zhuang1, Frank Li1, Lynn Miao1, Michael D Bartberger1, Tiffany L Correll1, David Chow1, Simon Wong1, Jian Luo1, Daniel C-H Lin1, Julio C Medina1.   

Abstract

GPR40 (FFAR1 or FFA1) is a target of high interest being pursued to treat type II diabetes due to its unique mechanism leading to little risk of hypoglycemia. We recently reported the discovery of AM-1638 (2), a potent full agonist of GPR40. In this report, we present the discovery of GPR40 full agonists containing conformationally constrained tricyclic spirocycles and their structure-activity relationships leading to more potent agonists such as AM-5262 (26) with improved rat PK profile and general selectivity profile. AM-5262 enhanced glucose stimulated insulin secretion (mouse and human islets) and improved glucose homeostasis in vivo (OGTT in HF/STZ mice) when compared to AM-1638.

Entities:  

Keywords:  AM-1638; AM-5262; AMG 837; FFA1; FFAR1; GPR40; full agonist; spirocycles; tricyclic

Year:  2013        PMID： 24900707      PMCID： PMC4027505          DOI： 10.1021/ml300427u

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.345


  24 in total

1.  3-Substituted 3-(4-aryloxyaryl)-propanoic acids as GPR40 agonists.

Authors:  Shawn P Walsh; Alexandra Severino; Changyou Zhou; Jiafang He; Gui-Bai Liang; Carina P Tan; Jin Cao; George J Eiermann; Ling Xu; Gino Salituro; Andrew D Howard; Sander G Mills; Lihu Yang
Journal:  Bioorg Med Chem Lett       Date:  2011-04-08       Impact factor: 2.823

2.  Discovery of phenylpropanoic acid derivatives containing polar functionalities as potent and orally bioavailable G protein-coupled receptor 40 agonists for the treatment of type 2 diabetes.

Authors:  Satoshi Mikami; Shuji Kitamura; Nobuyuki Negoro; Shinobu Sasaki; Masami Suzuki; Yoshiyuki Tsujihata; Takeshi Miyazaki; Ryo Ito; Nobuhiro Suzuki; Junichi Miyazaki; Takashi Santou; Naoyuki Kanzaki; Miyuki Funami; Toshimasa Tanaka; Tsuneo Yasuma; Yu Momose
Journal:  J Med Chem       Date:  2012-04-11       Impact factor: 7.446

3.  Synthesis and activity of small molecule GPR40 agonists.

Authors:  Dulce M Garrido; David F Corbett; Kate A Dwornik; Aaron S Goetz; Thomas R Littleton; Steve C McKeown; Wendy Y Mills; Terrence L Smalley; Celia P Briscoe; Andrew J Peat
Journal:  Bioorg Med Chem Lett       Date:  2006-01-24       Impact factor: 2.823

4.  Identification of fused-ring alkanoic acids with improved pharmacokinetic profiles that act as G protein-coupled receptor 40/free fatty acid receptor 1 agonists.

Authors:  Nobuyuki Negoro; Shinobu Sasaki; Masahiro Ito; Shuji Kitamura; Yoshiyuki Tsujihata; Ryo Ito; Masami Suzuki; Koji Takeuchi; Nobuhiro Suzuki; Junichi Miyazaki; Takashi Santou; Tomoyuki Odani; Naoyuki Kanzaki; Miyuki Funami; Toshimasa Tanaka; Tsuneo Yasuma; Yu Momose
Journal:  J Med Chem       Date:  2012-02-10       Impact factor: 7.446

5.  Identification of a potent and selective free fatty acid receptor 1 (FFA1/GPR40) agonist with favorable physicochemical and in vitro ADME properties.

Authors:  Elisabeth Christiansen; Christian Urban; Manuel Grundmann; Maria E Due-Hansen; Ellen Hagesaether; Johannes Schmidt; Leonardo Pardo; Susanne Ullrich; Evi Kostenis; Matthias Kassack; Trond Ulven
Journal:  J Med Chem       Date:  2011-09-13       Impact factor: 7.446

6.  Discovery of 5-aryloxy-2,4-thiazolidinediones as potent GPR40 agonists.

Authors:  Changyou Zhou; Cheng Tang; Eric Chang; Min Ge; Songnian Lin; Eric Cline; Carina P Tan; Yue Feng; Yun-Ping Zhou; George J Eiermann; Aleksandr Petrov; Gino Salituro; Peter Meinke; Ralph Mosley; Taro E Akiyama; Monica Einstein; Sanjeev Kumar; Joel Berger; Andrew D Howard; Nancy Thornberry; Sander G Mills; Lihu Yang
Journal:  Bioorg Med Chem Lett       Date:  2009-10-15       Impact factor: 2.823

7.  Discovery of potent and selective agonists for the free fatty acid receptor 1 (FFA(1)/GPR40), a potential target for the treatment of type II diabetes.

Authors:  Elisabeth Christiansen; Christian Urban; Nicole Merten; Kathrin Liebscher; Kasper K Karlsen; Alexandra Hamacher; Andreas Spinrath; Andrew D Bond; Christel Drewke; Susanne Ullrich; Matthias U Kassack; Evi Kostenis; Trond Ulven
Journal:  J Med Chem       Date:  2008-11-27       Impact factor: 7.446

8.  A potent class of GPR40 full agonists engages the enteroinsular axis to promote glucose control in rodents.

Authors:  Jian Luo; Gayathri Swaminath; Sean P Brown; Jane Zhang; Qi Guo; Michael Chen; Kathy Nguyen; Thanhvien Tran; Lynn Miao; Paul J Dransfield; Marc Vimolratana; Jonathan B Houze; Simon Wong; Maria Toteva; Bei Shan; Frank Li; Run Zhuang; Daniel C-H Lin
Journal:  PLoS One       Date:  2012-10-09       Impact factor: 3.240

9.  Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus.

Authors:  Ralph A Defronzo
Journal:  Diabetes       Date:  2009-04       Impact factor: 9.461

10.  Identification and pharmacological characterization of multiple allosteric binding sites on the free fatty acid 1 receptor.

Authors:  Daniel C-H Lin; Qi Guo; Jian Luo; Jane Zhang; Kathy Nguyen; Michael Chen; Thanh Tran; Paul J Dransfield; Sean P Brown; Jonathan Houze; Marc Vimolratana; Xian Yun Jiao; Yingcai Wang; Nigel J M Birdsall; Gayathri Swaminath
Journal:  Mol Pharmacol       Date:  2012-08-02       Impact factor: 4.054
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  9 in total

1.  Design and Synthesis of Novel, Selective GPR40 AgoPAMs.

Authors:  Christopher W Plummer; Matthew J Clements; Helen Chen; Murali Rajagopalan; Hubert Josien; William K Hagmann; Michael Miller; Maria E Trujillo; Melissa Kirkland; Daniel Kosinski; Joel Mane; Michele Pachanski; Boonlert Cheewatrakoolpong; Andrew F Nolting; Robert Orr; Melodie Christensen; Louis-Charles Campeau; Michael J Wright; Randal Bugianesi; Sarah Souza; Xiaoping Zhang; Jerry Di Salvo; Adam B Weinglass; Richard Tschirret-Guth; Ravi Nargund; Andrew D Howard; Steven L Colletti
Journal:  ACS Med Chem Lett       Date:  2017-01-23       Impact factor: 4.345

2.  Structure-Activity Relationship of Novel and Selective Biaryl-Chroman GPR40 AgoPAMs.

Authors:  Helen Y Chen; Christopher W Plummer; Dong Xiao; Harry R Chobanian; Duane DeMong; Michael Miller; Maria E Trujillo; Melissa Kirkland; Daniel Kosinski; Joel Mane; Michele Pachanski; Boonlert Cheewatrakoolpong; Jerry Di Salvo; Brande Thomas-Fowlkes; Sarah Souza; Daniel A Tatosian; Qing Chen; Michael J Hafey; Robert Houle; Andrew F Nolting; Robert Orr; Juliann Ehrhart; Adam B Weinglass; Richard Tschirret-Guth; Andrew D Howard; Steven L Colletti
Journal:  ACS Med Chem Lett       Date:  2018-06-14       Impact factor: 4.345

3.  Discovery of AM-6226: A Potent and Orally Bioavailable GPR40 Full Agonist That Displays Efficacy in Nonhuman Primates.

Authors:  Sean P Brown; Paul Dransfield; Marc Vimolratana; Liusheng Zhu; Jian Luo; Jane Zhang; XianYun Jiao; Vatee Pattaropong; Simon Wong; Run Zhuang; Gayathri Swaminath; Jonathan B Houze; Daniel C-H Lin
Journal:  ACS Med Chem Lett       Date:  2018-06-06       Impact factor: 4.345

4.  Improving the Pharmacokinetics of GPR40/FFA1 Full Agonists.

Authors:  Xiaohui Du; Paul J Dransfield; Daniel C-H Lin; Simon Wong; Yingcai Wang; Zhongyu Wang; Todd Kohn; Ming Yu; Sean P Brown; Marc Vimolratana; Liusheng Zhu; An-Rong Li; Yongli Su; Xianyun Jiao; Jiwen Jim Liu; Gayathri Swaminath; Thanhvien Tran; Jian Luo; Run Zhuang; Jane Zhang; Qi Guo; Frank Li; Richard Connors; Julio C Medina; Jonathan B Houze
Journal:  ACS Med Chem Lett       Date:  2014-02-03       Impact factor: 4.345

Review 5.  Targeting lipid GPCRs to treat type 2 diabetes mellitus - progress and challenges.

Authors:  Julien Ghislain; Vincent Poitout
Journal:  Nat Rev Endocrinol       Date:  2021-01-25       Impact factor: 43.330

6.  GPR40 (FFAR1) - Combined Gs and Gq signaling in vitro is associated with robust incretin secretagogue action ex vivo and in vivo.

Authors:  Maria Hauge; Marie A Vestmar; Anna S Husted; Jeppe P Ekberg; Michael J Wright; Jerry Di Salvo; Adam B Weinglass; Maja S Engelstoft; Andreas N Madsen; Michael Lückmann; Michael W Miller; Maria E Trujillo; Thomas M Frimurer; Birgitte Holst; Andrew D Howard; Thue W Schwartz
Journal:  Mol Metab       Date:  2014-10-24       Impact factor: 7.422

Review 7.  Long Chain Fatty Acids as Modulators of Immune Cells Function: Contribution of FFA1 and FFA4 Receptors.

Authors:  Maria A Hidalgo; Maria D Carretta; Rafael A Burgos
Journal:  Front Physiol       Date:  2021-07-01       Impact factor: 4.566

Review 8.  Treatment of type 2 diabetes by free Fatty Acid receptor agonists.

Authors:  Kenneth R Watterson; Brian D Hudson; Trond Ulven; Graeme Milligan
Journal:  Front Endocrinol (Lausanne)       Date:  2014-08-28       Impact factor: 5.555

9.  Vascular, but not luminal, activation of FFAR1 (GPR40) stimulates GLP-1 secretion from isolated perfused rat small intestine.

Authors:  Louise W Christensen; Rune E Kuhre; Charlotte Janus; Berit Svendsen; Jens J Holst
Journal:  Physiol Rep       Date:  2015-09
  9 in total

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