- Design, synthesis, and evaluation of fused heterocyclic analogs of SCH 58261 as adenosine A2A receptor antagonists
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SCH 58261 is a reported adenosine A2A receptor antagonist which is active in rat in vivo models of Parkinson's Disease upon ip administration. However, it has poor selectivity versus the A1 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 A2A receptor binding selectivity and pharmacokinetic properties. In particular, the tetrahydronaphthyridine 4s has excellent A2A 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 μM at physiological pH.
- 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.
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scheme or table
p. 4204 - 4209
(2009/04/10)
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- USE OF ION CHANNEL MODULATORS IN THE PROPHYLAXIS AND TREATMENT OF INFLAMMATORY AND IMMUNOLOGICAL DISEASES
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Use of compounds of general formula (1) and pharmacologically acceptable salts and prodrugs thereof:Formula (1) wherein A and B are CH2 or CH2CH2, R1 is hydrogen, alkyl, cycloalkyl, aryl, aralkyl or heteroaralkyl, R2, R3 and R4 are selected from hydrogen, alkyl, halogen, haloalkyl, alkoxy, alkoxycarbonyl, carboxyl, hydroxyl or cyano; X is R5CO, R5SO2, R5R7NCO, R5R7NSO2, R5SO2NR7CO or CO2R8, Y is R6CO, R6SO2, R6R7NCO, R6R7NSO2, R6SO2NR7CO or CO2R8, R5 and R6 are hydrogen, alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl, R7 is hydrogen, alkyl, aryl or aralkyl, and R8 is alkyl, aryl, aralkyl, alkoxyalkyl, heteroaryl or heteroarylalkyl, provided that when X is R5CO or R5SO2, then Y is not R6CO, R6SO2 or R6R7NCO, in the manufacture of a medicament for the prophylaxis or treatment of inflammatory or immunological disease.
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Page/Page column 39-45
(2010/11/30)
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- Synthesis and biological evaluation of benzazepine oxazolidinone antibacterials
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Novel benzazepine oxazolidinone antibacterials were synthesized and evaluated against clinically relevant susceptible and resistant organisms. The effect of ring nitrogen position and N-substitution on antibacterial activity is examined.
- Johnson, Paul D.,Aristoff, Paul A.,Zurenko, Gary E.,Schaadt, Ronda D.,Yagi, Betty H.,Ford, Charles W.,Hamel, Judith C.,Stapert, Douglas,Moerman, Judy K.
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p. 4197 - 4200
(2007/10/03)
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