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

M Phelps Grella, R Danso-Danquah, M K Safo, G S Joshi, J Kister, M Marden, S J Hoffman, D J Abraham

Department of Medicinal Chemistry, School of Pharmacy, Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, Virginia 23298-0133, USA.

Journal of medicinal chemistry 2000 Dec 14

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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.

Citation

M Phelps Grella, R Danso-Danquah, M K Safo, G S Joshi, J Kister, M Marden, S J Hoffman, D J Abraham. Synthesis and structure-activity relationships of chiral allosteric modifiers of hemoglobin. Journal of medicinal chemistry. 2000 Dec 14;43(25):4726-37