Shah Unmesh, Lankin Claire M, Boyle Craig D, Chackalamannil Samuel, Greenlee William J, Neustadt Bernard R, Cohen-Williams Mary E, Higgins Guy A, Ng Kwokei, Varty Geoffrey B, Zhang Hongtao, Lachowicz Jean E
Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Bioorg Med Chem Lett. 2008 Jul 15;18(14):4204-9. doi: 10.1016/j.bmcl.2008.05.069. Epub 2008 May 22.
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.
