Synthesis and SAR of novel GPR39 agonists and positive allosteric modulators

被引：2

作者：

Burley, Russell ^{[1
]}

Hewer, Richard C. ^{[1
]}

Teall, Martin ^{[1
]}

Dickson, Louise ^{[1
]}

Ossola, Bernardino ^{[1
]}

Russell, Sam ^{[1
]}

Bender, Clare ^{[1
]}

Cheung, Toni ^{[1
]}

Powell, Justin A. C. ^{[1
]}

Xu, Xiao ^{[1
]}

Brice, Nicola ^{[1
]}

Otter, Lucy ^{[1
]}

Arimont, Marta L. ^{[2
]}

Kidd, Sarah ^{[2
]}

Vidal, David ^{[2
]}

Dale, James W. ^{[2
]}

Mervin, Lewis ^{[2
]}

Sore, Hannah F. ^{[2
]}

Mateu, Natalia ^{[2
]}

Lakshminarayana, Narayana ^{[3
]}

Dawson, Lee A. ^{[1
]}

Carlton, Mark ^{[1
]}

Buerli, Roland W. ^{[1
]}

机构：

[1] Cerevance Ltd, 418 Cambridge Sci Pk,Milton Rd, Cambridge, Cambs, England

[2] PharmEnable Ltd, 2 Hazlewell Court,Bar Rd, Cambridge, Cambs, England

[3] Aragen Life Sci Ltd, Plot 284A Part,Bommasandra Jigani Link Rd Ind A, Bengaluru 562106, India

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2022年 / 61卷

关键词：

GPR39; G protein-coupled receptor; Agonist; Parkinson 's disease; RECEPTOR; DISCOVERY;

D O I：

10.1016/j.bmcl.2022.128607

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We report a significant decrease in transcription of the G protein-coupled receptor GPR39 in striatal neurons of Parkinson's disease patients compared to healthy controls, suggesting that a positive modulator of GPR39 may beneficially impact neuroprotection. To test this notion, we developed various structurally diverse tool molecules. While we elaborated on previously reported starting points, we also performed an in silico screen which led to completely novel pharmacophores. In vitro studies indicated that GPR39 agonism does not have a profound effect on neuroprotection.

引用

页数：7

共 50 条

[1] Discovery and Characterization of Novel GPR39 Agonists Allosterically Modulated by Zinc
Sato, Seiji
Huang, Xi-Ping
Kroeze, Wesley K.
Roth, Bryan L.
MOLECULAR PHARMACOLOGY, 2016, 90 (06) : 726 - 737
[2] GI functions of GPR39: novel biology
Depoortere, Inge
CURRENT OPINION IN PHARMACOLOGY, 2012, 12 (06) : 647 - 652
[3] The pathophysiological functions and therapeutic potential of GPR39: Focus on agonists and antagonists
Cheng, Yuhui
Zhao, Chang
Bin, Yan
Liu, Yuan
Cheng, Lin
Xia, Fan
Tian, Xiaowen
Liu, Xinlei
Liu, Sicen
Ying, Binwu
Shao, Zhenhua
Yan, Wei
INTERNATIONAL IMMUNOPHARMACOLOGY, 2024, 143
[4] Discovery of 2-Pyridylpyrimidines as the First Orally Bioavailable GPR39 Agonists
Peukert, Stefan
Hughes, Richard
Nunez, Jill
He, Guo
Yan, Zhao
Jain, Rishi
Llamas, Luis
Luchansky, Sarah
Carlson, Adam
Liang, Guiqing
Kunjathoor, Vidya
Pietropaolo, Mike
Shapiro, Jeffrey
Castellana, Anja
Wu, Xiaoping
Bose, Avirup
ACS MEDICINAL CHEMISTRY LETTERS, 2014, 5 (10): : 1114 - 1118
[5] Identification of novel GPR39 agonists that stimulate insulin and GLP-1 secretion in vitro using StaR® technology
Mace, O. J.
Andrews, S.
Brown, A. J. H.
Brown, S.
Congreve, M.
Jazayeri, A.
Patel, J.
Prihandoko, R.
Tehan, B.
Marshall, F.
DIABETOLOGIA, 2013, 56 : S264 - S265
[6] Novel Zn2+ Modulated GPR39 Receptor Agonists Do Not Drive Acute Insulin Secretion in Rodents
Fjellstrom, Ola
Larsson, Niklas
Yasuda, Shin-ichiro
Tsuchida, Takuma
Oguma, Takahiro
Marley, Anna
Wennberg-Huldt, Charlotte
Hovdal, Daniel
Fukuda, Hajime
Yoneyama, Yukimi
Sasaki, Kazuyo
Johansson, Anders
Lundqvist, Sara
Brengdahl, Johan
Isaacs, Richard J.
Brown, Daniel
Geschwindner, Stefan
Benthem, Lambertus
Priest, Claire
Turnbull, Andrew
PLOS ONE, 2015, 10 (12):
[7] Synthesis and SAR of piperazinyl and homopiperazinyl analogs as positive allosteric modulators of mGluR4
Cheung, Yiu-Yin
Hopkins, Corey R.
Niswender, Colleen
Lindsley, Craig W.
Conn, P. Jeffrey
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2010, 240
[8] Group II metabotropic glutamate receptor agonists and positive allosteric modulators as novel treatments for schizophrenia
Fell, Matthew J.
McKinzie, David L.
Monn, James A.
Svensson, Kjell A.
NEUROPHARMACOLOGY, 2012, 62 (03) : 1473 - 1483
[9] Novel positive allosteric modulators of GABAA receptors
Sigel, E
Dodd, RH
DRUGS OF THE FUTURE, 2001, 26 (12) : 1191 - 1197
[10] Novel AMPA receptor allosteric modulators of bis(pyrimidine) series: synthesis and SAR evaluation
Sedenkova, Kseniya N.
Kositov, Sergey V.
Zverev, Denis V.
Radchenko, Eugene V.
Grishin, Yuri K.
Gabrel'yan, Alexey V.
Zamoyski, Vladimir L.
Grigoriev, Vladimir V.
Averina, Elena B.
Palyulin, Vladimir A.
MENDELEEV COMMUNICATIONS, 2024, 34 (01) : 8 - 10

← 1 2 3 4 5 →