2,6-Diaryl-4-phenacylaminopyrimidines as potent and selective adenosine A(2A) antagonists with reduced hERG liability.
In this report, the design and synthesis of a series of pyrimidine based adenosine A(2A) antagonists are described. The strategy and outcome of expanding SAR exploration to attenuate hERG and improve selectivity over A(1) are discussed. Compound 33 exhibited excellent potency, selectivity over A(1), and reduced hERG liability.
Moorjani
Manisha
M
Department of Medicinal Chemistry, Neurocrine Biosciences, 12790 El Camino Real, San Diego, CA 92130, USA.
Zhang
Xiaohu
X
Chen
Yongsheng
Y
Lin
Emily
E
Rueter
Jaimie K
JK
Gross
Raymond S
RS
Lanier
Marion C
MC
Tellew
John E
JE
Williams
John P
JP
Lechner
Sandra M
SM
Malany
Siobhan
S
Santos
Mark
M
Ekhlassi
Paddi
P
Castro-Palomino
Julio C
JC
Crespo
María I
MI
Prat
Maria
M
Gual
Silvia
S
Díaz
José-Luis
JL
Saunders
John
J
Slee
Deborah H
DH
D058917:Adenosine A2 Receptor Antagonists; D002460:Cell Line; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D015195:Drug Design; D006801:Humans; D007700:Kinetics; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D043705:Receptor, Adenosine A2A / Q000378:metabolism; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000037:antagonists & inhibitors*; D000071230:Transcriptional Regulator ERG
D058917:Adenosine A2 Receptor Antagonists; D065692:Cytochrome P-450 CYP3A Inhibitors; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human