N-[6-amino-2-(heteroaryl)pyrimidin-4-yl]acetamides as A2A receptor antagonists with improved drug like properties and in vivo efficacy

Journal of Medicinal Chemistry
Marion C LanierDeborah H Slee

Abstract

In the present article, we report on a strategy to improve the physical properties of a series of small molecule human adenosine 2A (hA2A) antagonists. One of the aromatic rings typical of this series of antagonists is replaced with a series of aliphatic groups, with the aim of disrupting crystal packing of the molecule to lower the melting point and in turn to improve the solubility. Herein, we describe the SAR of a new series of water-soluble 2,4,6-trisubstituted pyrimidines where R1 is an aromatic heterocycle, R2 is a short-chain alkyl amide, and the typical R3 aromatic heterocyclic substituent is replaced with an aliphatic amino substituent. This approach significantly enhanced aqueous solubility and lowered the log P of the system to provide molecules without significant hERG or CYP liabilities and robust in vivo efficacy.

References

Feb 7, 2003·Current Topics in Medicinal Chemistry·Gloria CristalliRosaria Volpini
Feb 7, 2003·Current Topics in Medicinal Chemistry·Barbara CacciariGiampiero Spalluto
Apr 28, 2004·Drug Discovery Today·Andrew L HopkinsAlexander Alex
Mar 2, 2005·Pharmacology & Therapeutics·Kui XuMichael Schwarzschild
Jul 12, 2005·Expert Opinion on Investigational Drugs·Peter Jenner
Dec 16, 2006·Current Medicinal Chemistry·O Yuzlenko, K Kieć-Kononowicz

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Citations

Mar 6, 2012·Journal of Receptor and Signal Transduction Research·Kiran Kumar MustyalaUma Vuruputuri
Jul 8, 2009·Organic & Biomolecular Chemistry·Marco RadiMaurizio Botta
Mar 31, 2015·Medicinal Research Reviews·Delia PretiKatia Varani
Jan 27, 2019·Current Medicinal Chemistry·Hayrettin Ozan GulcanIlkay Erdogan Orhan
Oct 30, 2013·Journal of Medicinal Chemistry·Manuel de Lera RuizJunying Zheng

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