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説明

Dolasetron was launched as Anzemet in Australia and the US for the prevention of nausea and vomiting in chemotherapy patients. It is a highly potent and very selective antagonist of 5-HT3 receptors ; it is the sixth in this class of compounds to be marketed for the treatment of chemotherapy-induced emesis. The last two approved in this class were Nazasetron (1994) and Ramosetron (1996). Anzemet was prepared by a seven step sequence from a cyclopentenecarboxylic ester via a Robinson-Schopf cyclisation of a dialdehyde into a key 9-azabicyclo[3.3.l]nonan-3-one. In a clinical study with 164 cancer patients treated with Dolasetron mesylate prior to Cisplatin, single doses of 10- 50 mg achieved major control of nausea and emesis in 73% of subjects and were well tolerated. Results from pharmacokinetic studies in humans showed that the clinical effects and duration of action seem to be due mainly to a major plasma metabolite rapidly formed and very potent itself, the (+) enantiomeric alcohol obtained by enzymatic reduction of the cyclic ketone.