2,6-Diaryl-4-acylaminopyrimidines as potent and selective adenosine A(2A) antagonists with improved solubility and metabolic stability.
In this report, the strategy and outcome of expanding SAR exploration to improve solubility and metabolic stability are discussed. Compound 35 exhibited excellent potency, selectivity over A(1) and improved solubility of >4 mg/mL at pH 8.0. In addition, compound 35 had good metabolic stability with a scaled intrinsic clearance of 3 mL/min/kg (HLM) and demonstrated efficacy in the haloperidol induced catalepsy model.
Moorjani
Manisha
M
Department of Medicinal Chemistry, Neurocrine Biosciences, 12780 El Camino Real, San Diego, CA 92130, USA. mmoorjani@neurocrine.com
Luo
Zhiyong
Z
Lin
Emily
E
Vong
Binh G
BG
Chen
Yongsheng
Y
Zhang
Xiaohu
X
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
Crespo
María I
MI
Díaz
José-Luis
JL
Saunders
John
J
Slee
Deborah H
DH
D058917:Adenosine A2 Receptor Antagonists; D000631:Aminopyridines / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D006220:Haloperidol / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D010300:Parkinson Disease / Q000628:therapy; D011485:Protein Binding; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D043682:Receptor, Adenosine A1 / Q000737:chemistry; D043705:Receptor, Adenosine A2A / Q000737:chemistry; D012995:Solubility; D013329:Structure-Activity Relationship
D058917:Adenosine A2 Receptor Antagonists; D000631:Aminopyridines; D011743:Pyrimidines; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A; D006220:Haloperidol