title: Identification of novel, water-soluble, 2-amino-N-pyrimidin-4-yl acetamides as A2A receptor antagonists with in vivo efficacy.
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.
authors.affiliation: Department of Medicinal Chemistry, Pharmacology and Lead Discovery, Neuroscience, Chemical Development and Preclinical Development, Neurocrine Biosciences, San Diego, CA 92130, USA. dslee@neurocrine.com
authors.forename: Deborah H
authors.initials: DH
authors.lastname: Slee
authors.forename: Xiaohu
authors.initials: X
authors.lastname: Zhang
authors.forename: Manisha
authors.initials: M
authors.lastname: Moorjani
authors.forename: Emily
authors.initials: E
authors.lastname: Lin
authors.forename: Marion C
authors.initials: MC
authors.lastname: Lanier
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Chen
authors.forename: Jaimie K
authors.initials: JK
authors.lastname: Rueter
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Lechner
authors.forename: Stacy
authors.initials: S
authors.lastname: Markison
authors.forename: Siobhan
authors.initials: S
authors.lastname: Malany
authors.forename: Tanya
authors.initials: T
authors.lastname: Joswig
authors.forename: Mark
authors.initials: M
authors.lastname: Santos
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Gross
authors.forename: John P
authors.initials: JP
authors.lastname: Williams
authors.forename: Julio C
authors.initials: JC
authors.lastname: Castro-Palomino
authors.forename: María I
authors.initials: MI
authors.lastname: Crespo
authors.forename: Maria
authors.initials: M
authors.lastname: Prat
authors.forename: Silvia
authors.initials: S
authors.lastname: Gual
authors.forename: José-Luis
authors.initials: JL
authors.lastname: Díaz
authors.forename: Jenny
authors.initials: J
authors.lastname: Wen
authors.forename: Zhihong
authors.initials: Z
authors.lastname: O'Brien
authors.forename: John
authors.initials: J
authors.lastname: Saunders
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D000978:Antiparkinson Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002375:Catalepsy / Q000139:chemically induced / Q000523:psychology; D002460:Cell Line; D003001:Cloning, Molecular; D006224:Cricetinae; D003412:Cricetulus; D006220:Haloperidol; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects; D043705:Receptor, Adenosine A2A / Q000235:genetics; D012995:Solubility; D013329:Structure-Activity Relationship; D014867:Water
chemical_list: D000081:Acetamides; D058917:Adenosine A2 Receptor Antagonists; D000978:Antiparkinson Agents; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A; D014867:Water; D006220:Haloperidol