Synthesis and structure-activity relationships of chiral allosteric modifiers of hemoglobin

A series of allosteric effecters of hemoglobin, 2-(aryloxy)-2-alkanoic acid s, was prepared to investigate the effect of the stereocenter on allosteric activity. The chiral analogues were based on the lead compound, RSR13 (3b) , with different alkyl/alkanoic and cycloalkyl/cycloalkanoic groups positio ned at the acidic chiral center. Of the 23 racemic molecules synthesized, 5 were selected for resolution based on structure-activity relationships. On e chiral analogue, (-)( 1R,2R)-1-[4-[[(3,5 -dimethylanilino)carbonyl]methyl ]phenoxy]-2-methylcyclopentanecarboxylic acid (11), exhibited greater in vi tro activity in hemoglobin solutions than its antipode, racemate, and RSR13 . Compound (-)-(LR,2R)-11 was equipotent with RSR13 in whole blood, is a ca ndidate for in vivo animal studies, and if efficacious and safe has a poten tial for use in humans. In general, it was found that chirality affects all osteric effector activity with measurable differences observed between enan tiomers and the racemates.