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  • Title: Synthesis and structure-activity relationships of chiral allosteric modifiers of hemoglobin.
    Author: Phelps Grella M, Danso-Danquah R, Safo MK, Joshi GS, Kister J, Marden M, Hoffman SJ, Abraham DJ.
    Journal: J Med Chem; 2000 Dec 14; 43(25):4726-37. PubMed ID: 11123981.
    Abstract:
    A series of allosteric effectors of hemoglobin, 2-(aryloxy)-2-alkanoic acids, 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 positioned at the acidic chiral center. Of the 23 racemic molecules synthesized, 5 were selected for resolution based on structure-activity relationships. One chiral analogue, (-)-(1R,2R)-1-[4-[[(3, 5-dimethylanilino)carbonyl]methyl]phenoxy]-2-methylcyclopentane carbox ylic 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 in humans. In general, it was found that chirality affects allosteric effector activity with measurable differences observed between enantiomers and the racemates.
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