Design, synthesis, and evaluation of fused heterocyclic analogs of SCH 58261 as adenosine A2A receptor antagonists.
SCH 58261 is a reported adenosine A(2A) receptor antagonist which is active in rat in vivo models of Parkinson's Disease upon ip administration. However, it has poor selectivity versus the A(1) receptor and does not demonstrate oral activity. Quinoline analogs have improved upon the selectivity and pharmacokinetics of SCH 58261, but were difficult to handle due to poor aqueous solubility. We report the design and synthesis of fused heterocyclic analogs of SCH 58261 with aqueous solubility as well as improved A(2A) receptor binding selectivity and pharmacokinetic properties. In particular, the tetrahydronaphthyridine 4s has excellent A(2A) receptor in vitro binding affinity and selectivity, is active orally in a rat in vivo model of Parkinson's Disease, and has aqueous solubility of 100 microM at physiological pH.
Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Unmesh
U
Shah
Claire M
CM
Lankin
Craig D
CD
Boyle
Samuel
S
Chackalamannil
William J
WJ
Greenlee
Bernard R
BR
Neustadt
Mary E
ME
Cohen-Williams
Guy A
GA
Higgins
Kwokei
K
Ng
Geoffrey B
GB
Varty
Hongtao
H
Zhang
Jean E
JE
Lachowicz
D000241:Adenosine / Q000737:chemistry; D058917:Adenosine A2 Receptor Antagonists; D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004195:Disease Models, Animal; D015195:Drug Design; D006863:Hydrogen-Ion Concentration; D008956:Models, Chemical; D010300:Parkinson Disease / Q000188:drug therapy*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D012995:Solubility; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D014867:Water / Q000737:chemistry
C098657:5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine; D058917:Adenosine A2 Receptor Antagonists; D011743:Pyrimidines; D014230:Triazoles; D014867:Water; D000241:Adenosine