Chiral resolution and absolute configuration of the enantiomers of 5-acetyl-2-methyl-4-methylsulfinyl-6-phenyl-3(2H)-pyridazinone and evaluation of their platelet aggregation inhibitory activity.
In a series of 5-acyl-6-phenyl-2,4-substituted-3(2H)-pyridaziones the derivative 1a, with a sulfur stereogenic center, had the most potent activity as human platelet aggregation inhibitor. The resolution of rac-1a was successfully performed by chiral chromatography on Chiralcel OD-R, OD-H, and Chiralpak AD columns and scaled up to a preparative level. The absolute configuration of (-)-(S)-1a was determined by X-ray crystallographic analysis. In vitro human platelet aggregation inhibitory activity was evaluated. Both the enantiomers showed IC50 values in the same micromolar range, but the (-)-(S) isomer was slightly more potent [(S)/(R) potency ratio was 4/1].
Azzolina
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O
Dipartimento di Chimica Farmaceutica, Università di Pavia, Italy.
Dal Piaz
V
V
Collina
S
S
Giovannoni
M P
MP
Tadini
C
C
D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D006801:Humans; D066298:In Vitro Techniques; D008958:Models, Molecular; D008968:Molecular Conformation; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011724:Pyridazines / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D013237:Stereoisomerism
D010975:Platelet Aggregation Inhibitors; D011724:Pyridazines