title: 2,6-Diaryl-4-phenacylaminopyrimidines as potent and selective adenosine A(2A) antagonists with reduced hERG liability.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Neurocrine Biosciences, 12790 El Camino Real, San Diego, CA 92130, USA.
authors.forename: Manisha
authors.initials: M
authors.lastname: Moorjani
authors.forename: Xiaohu
authors.initials: X
authors.lastname: Zhang
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Chen
authors.forename: Emily
authors.initials: E
authors.lastname: Lin
authors.forename: Jaimie K
authors.initials: JK
authors.lastname: Rueter
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Gross
authors.forename: Marion C
authors.initials: MC
authors.lastname: Lanier
authors.forename: John E
authors.initials: JE
authors.lastname: Tellew
authors.forename: John P
authors.initials: JP
authors.lastname: Williams
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Lechner
authors.forename: Siobhan
authors.initials: S
authors.lastname: Malany
authors.forename: Mark
authors.initials: M
authors.lastname: Santos
authors.forename: Paddi
authors.initials: P
authors.lastname: Ekhlassi
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: John
authors.initials: J
authors.lastname: Saunders
authors.forename: Deborah H
authors.initials: DH
authors.lastname: Slee
mesh_terms: 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
chemical_list: 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