Oxime derivatives of PD217015 and PD148903. Orally active anti-Parkinson cascade prodrugs
نویسندگان
چکیده
A series of oxime ether and oxime ester derivatives of the potential anti-Parkinson prodrug PD148903 (2.3) were synthesized and evaluated in pharmacological models. Oximes 4.3 (hydroxyl-oxime) and 4.4 (methoxyl-oxime) were inactive in vitro but in the Ungerstedt rat model for Parkinson’s disease 4.3 and 4.4 produced a pronounced and long lasting effect at 1.0 mg kg po. Enantiomerically pure (–)-4.3 and (–)-4.10 (acetyl-oxime) were prepared from 2.3a (= (–)-2.3) and produced a potent effect at 0.3 mg kg po. Large individual differences were observed in responsiveness between rats. The tosylated oxime (4.14) was found inactive up to 10 mg kg po. Though less potent than 2.3 itself, oxime derivatives of 2.3 can be orally active, most likely acting as cascade prodrugs.
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