(±)-Terodiline, the antianginal agent, perhaps represents the best authenticated example of a drug that had to be withdrawn from the world market as consequence of proven stereospecific toxicity. Terodiline has a close similarity to prenylamine from a structural and pharmacological view point.
It was firs marketed as an antianginal agent but it exhibited urinary retention as a frequent and worrying side-effect. It was decided to exploit the the side-effect. Therefore the drug was redeveloped and marketed in 1986 for clinical use in urinary incontinence (leaking urine by accident). Over a couple of years reports of serious cardiac toxicity started emerging following the clinical use of terodiline and some of them had a critical outcome. Because of these observations, in 1991, terodiline was withdrawn from the market world-wide
Chirality and drug withdrawals
Terodiline has one stereogenic center and exists as mirror-image twins. Terodiline being structurally related to prenylamine demonstrates enantioselective pharmacological effects. The calcium agonist activity remains predominantly in the (S)-(-)-terodiline, whereas the anticholinergic actions is found in the (R)-(+)-enantiomer. Both the pharmacodynamic actions possibly contribute to the overall therapeutic effect to a variable extent.
Enantioselective studies has shown that the (R )-(+)-terodiline is responsible for the prolongation of the QT interval associated with the racemic terodiline. Hence, the (R)-enantiomer is found to be the culprit for the serious ventricular tachyarrhythmias observed with the clinical use of this drug.
Nomenclature
(RS)-N-tert-butyl-4,4-diphenylbutan-2-amine (RS)-N-tert-Butyl-1-methyl-3,3-diphenylpropylamine
Therapeutic category
Antianginal and treat urinary incontinence – Withdrawn from world market due to stereospecific toxicity
Exercise
Learn to draw stereochemical structure, understand stereo-descriptors employed in the nomenclature system
References
https://pubchem.ncbi.nlm.nih.gov/compound/Terodiline
Eichelbaum, Michel F., Testa, Bernard, Somogyi, Andrew (Eds.). Stereochemical aspects of drug action and disposition, Springer, Page 401-32, 2003.
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