Identification of novel, water-soluble, 2-amino-N-pyrimidin-4-yl acetamides as A2A receptor antagonists with in vivo efficacy.
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.
Slee
Deborah H
DH
Department of Medicinal Chemistry, Pharmacology and Lead Discovery, Neuroscience, Chemical Development and Preclinical Development, Neurocrine Biosciences, San Diego, CA 92130, USA. dslee@neurocrine.com
Zhang
Xiaohu
X
Moorjani
Manisha
M
Lin
Emily
E
Lanier
Marion C
MC
Chen
Yongsheng
Y
Rueter
Jaimie K
JK
Lechner
Sandra M
SM
Markison
Stacy
S
Malany
Siobhan
S
Joswig
Tanya
T
Santos
Mark
M
Gross
Raymond S
RS
Williams
John P
JP
Castro-Palomino
Julio C
JC
Crespo
María I
MI
Prat
Maria
M
Gual
Silvia
S
Díaz
José-Luis
JL
Wen
Jenny
J
O'Brien
Zhihong
Z
Saunders
John
J
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
D000081:Acetamides; D058917:Adenosine A2 Receptor Antagonists; D000978:Antiparkinson Agents; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A; D014867:Water; D006220:Haloperidol