Literature DB >> 18189346

Identification of novel, water-soluble, 2-amino-N-pyrimidin-4-yl acetamides as A2A receptor antagonists with in vivo efficacy.

Deborah H Slee1, Xiaohu Zhang, Manisha Moorjani, Emily Lin, Marion C Lanier, Yongsheng Chen, Jaimie K Rueter, Sandra M Lechner, Stacy Markison, Siobhan Malany, Tanya Joswig, Mark Santos, Raymond S Gross, John P Williams, Julio C Castro-Palomino, María I Crespo, Maria Prat, Silvia Gual, José-Luis Díaz, Jenny Wen, Zhihong O'Brien, John Saunders.   

Abstract

Potent adenosine hA2A receptor antagonists are often accompanied by poor aqueous solubility, which presents issues for drug development. Herein we describe the early exploration of the structure-activity relationships of a lead pyrimidin-4-yl acetamide series to provide potent and selective 2-amino-N-pyrimidin-4-yl acetamides as hA2A receptor antagonists with excellent aqueous solubility. In addition, this series of compounds has demonstrated good bioavailability and in vivo efficacy in a rodent model of Parkinson's disease, despite having reduced potency for the rat A2A receptor versus the human A2A receptor.

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Year:  2008        PMID： 18189346     DOI： 10.1021/jm070623o

Source DB:  PubMed          Journal:  J Med Chem        ISSN： 0022-2623            Impact factor:   7.446


  9 in total

1.  Discovery, synthesis, and structure-activity relationship development of a series of N-4-(2,5-dioxopyrrolidin-1-yl)phenylpicolinamides (VU0400195, ML182): characterization of a novel positive allosteric modulator of the metabotropic glutamate receptor 4 (mGlu(4)) with oral efficacy in an antiparkinsonian animal model.

Authors:  Carrie K Jones; Darren W Engers; Analisa D Thompson; Julie R Field; Anna L Blobaum; Stacey R Lindsley; Ya Zhou; Rocco D Gogliotti; Satyawan Jadhav; Rocio Zamorano; Jim Bogenpohl; Yoland Smith; Ryan Morrison; J Scott Daniels; C David Weaver; P Jeffrey Conn; Craig W Lindsley; Colleen M Niswender; Corey R Hopkins
Journal:  J Med Chem       Date:  2011-10-19       Impact factor: 7.446

2.  The Discovery and Characterization of ML218: A Novel, Centrally Active T-Type Calcium Channel Inhibitor with Robust Effects in STN Neurons and in a Rodent Model of Parkinson's Disease.

Authors:  Zixiu Xiang; Analisa D Thompson; John T Brogan; Michael L Schulte; Bruce J Melancon; Debbie Mi; L Michelle Lewis; Bende Zou; Liya Yang; Ryan Morrison; Tammy Santomango; Frank Byers; Katrina Brewer; Jonathan S Aldrich; Haibo Yu; Eric S Dawson; Min Li; Owen McManus; Carrie K Jones; J Scott Daniels; Corey R Hopkins; Ximin Simon Xie; P Jeffrey Conn; C David Weaver; Craig W Lindsley
Journal:  ACS Chem Neurosci       Date:  2011-12-21       Impact factor: 4.418

Review 3.  Recent progress on the identification of metabotropic glutamate 4 receptor ligands and their potential utility as CNS therapeutics.

Authors:  Albert J Robichaud; Darren W Engers; Craig W Lindsley; Corey R Hopkins
Journal:  ACS Chem Neurosci       Date:  2011-06-14       Impact factor: 4.418

4.  In Silico Studies Targeting G-protein Coupled Receptors for Drug Research Against Parkinson's Disease.

Authors:  Agostinho Lemos; Rita Melo; Antonio Jose Preto; Jose Guilherme Almeida; Irina Sousa Moreira; Maria Natalia Dias Soeiro Cordeiro
Journal:  Curr Neuropharmacol       Date:  2018       Impact factor: 7.363

5.  Optimization of 6-heterocyclic-2-(1H-pyrazol-1-yl)-N-(pyridin-2-yl)pyrimidin-4-amine as potent adenosine A2A receptor antagonists for the treatment of Parkinson's disease.

Authors:  Jiyue Zheng; Zhaohui Yang; Xuan Li; Linlang Li; Haikuo Ma; Meiyu Wang; Hongjian Zhang; Xuechu Zhen; Xiaohu Zhang
Journal:  ACS Chem Neurosci       Date:  2014-06-23       Impact factor: 4.418

6.  The metabotropic glutamate receptor 4-positive allosteric modulator VU0364770 produces efficacy alone and in combination with L-DOPA or an adenosine 2A antagonist in preclinical rodent models of Parkinson's disease.

Authors:  Carrie K Jones; Michael Bubser; Analisa D Thompson; Jonathan W Dickerson; Nathalie Turle-Lorenzo; Marianne Amalric; Anna L Blobaum; Thomas M Bridges; Ryan D Morrison; Satyawan Jadhav; Darren W Engers; Kimberly Italiano; Jacob Bode; J Scott Daniels; Craig W Lindsley; Corey R Hopkins; P Jeffrey Conn; Colleen M Niswender
Journal:  J Pharmacol Exp Ther       Date:  2011-11-16       Impact factor: 4.030

Review 7.  mGluR4-positive allosteric modulation as potential treatment for Parkinson's disease.

Authors:  Corey R Hopkins; Craig W Lindsley; Colleen M Niswender
Journal:  Future Med Chem       Date:  2009-06       Impact factor: 3.808

8.  Development and Antiparkinsonian Activity of VU0418506, a Selective Positive Allosteric Modulator of Metabotropic Glutamate Receptor 4 Homomers without Activity at mGlu2/4 Heteromers.

Authors:  Colleen M Niswender; Carrie K Jones; Xin Lin; Michael Bubser; Analisa Thompson Gray; Anna L Blobaum; Darren W Engers; Alice L Rodriguez; Matthew T Loch; J Scott Daniels; Craig W Lindsley; Corey R Hopkins; Jonathan A Javitch; P Jeffrey Conn
Journal:  ACS Chem Neurosci       Date:  2016-08-05       Impact factor: 4.418

Review 9.  Adenosine A(2A) Receptor Antagonists and Parkinson's Disease.

Authors:  Brian C Shook; Paul F Jackson
Journal:  ACS Chem Neurosci       Date:  2011-06-21       Impact factor: 4.418
  9 in total

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