Synthesis of N-pyrimidinyl-2-phenoxyacetamides as adenosine A2A receptor antagonists.
A series of N-pyrimidinyl-2-phenoxyacetamide adenosine A(2A) antagonists is described. SAR studies led to compound 14 with excellent potency (K(i) = 0.4 nM), selectivity (A(1)/A(2A) > 100), and efficacy (MED 10 mg/kg p.o.) in the rat haloperidol-induced catalepsy model for Parkinson's disease.
Zhang
Xiaohu
X
Department of Medicinal Chemistry, Neurocrine Biosciences, 12790 El Camino Real, San Diego, CA 92130, USA. litiger_99@yahoo.com
Rueter
Jaimie K
JK
Chen
Yongsheng
Y
Moorjani
Manisha
M
Lanier
Marion C
MC
Lin
Emily
E
Gross
Raymond S
RS
Tellew
John E
JE
Williams
John P
JP
Lechner
Sandra M
SM
Markison
Stacy
S
Joswig
Tanya
T
Malany
Siobhan
S
Santos
Mark
M
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; D000284:Administration, Oral; D000818:Animals; D000978:Antiparkinson Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002375:Catalepsy / Q000139:chemically induced / Q000517:prevention & control*; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004594:Electrophysiology; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D006220:Haloperidol / Q000633:toxicity; D006801:Humans; D015394:Molecular Structure; D010300:Parkinson Disease / Q000503:physiopathology*; D010642:Phenoxyacetates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
D058917:Adenosine A2 Receptor Antagonists; D000978:Antiparkinson Agents; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D051638:Ether-A-Go-Go Potassium Channels; C496884:KCNH1 protein, human; D010642:Phenoxyacetates; D011743:Pyrimidines; D003577:Cytochrome P-450 Enzyme System; C465260:Cyp3a2 protein, rat; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; D006220:Haloperidol