Identification of Novel, Water-Soluble, 2-Amino-N-pyrimidin-4-yl Acetamides as A_2AReceptor Antagonists with In Vivo Efficacy

Potent adenosine hA(2A) 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-pyrimidin4-yl acetamides as hA(2A) 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 A(2A) receptor versus the human A2A receptor.