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.
Department of Medicinal Chemistry, Neurocrine Biosciences, 12780 El Camino Real, San Diego, CA 92130, USA. mmoorjani@neurocrine.com
Manisha
M
Moorjani
Zhiyong
Z
Luo
Emily
E
Lin
Binh G
BG
Vong
Yongsheng
Y
Chen
Xiaohu
X
Zhang
Jaimie K
JK
Rueter
Raymond S
RS
Gross
Marion C
MC
Lanier
John E
JE
Tellew
John P
JP
Williams
Sandra M
SM
Lechner
Siobhan
S
Malany
Mark
M
Santos
María I
MI
Crespo
José-Luis
JL
Díaz
John
J
Saunders
Deborah H
DH
Slee
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