| Abstract
| - A series of allosteric effectors of hemoglobin, 2-(aryloxy)-2-alkanoic acids, was prepared toinvestigate the effect of the stereocenter on allosteric activity. The chiral analogues were basedon the lead compound, RSR13 (3b), with different alkyl/alkanoic and cycloalkyl/cycloalkanoicgroups positioned at the acidic chiral center. Of the 23 racemic molecules synthesized, 5 wereselected for resolution based on structure−activity relationships. One chiral analogue, (−)-(1R,2R)-1-[4-[[(3,5-dimethylanilino)carbonyl]methyl]phenoxy]-2-methylcyclopentanecarboxylic acid (11), exhibited greater in vitro activity in hemoglobin solutions than its antipode,racemate, and RSR13. Compound (−)-(1R,2R)-11 was equipotent with RSR13 in whole blood,is a candidate for in vivo animal studies, and if efficacious and safe has a potential for use inhumans. In general, it was found that chirality affects allosteric effector activity withmeasurable differences observed between enantiomers and the racemates.
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