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© 1990 Oxford University Press

other

Genetic Toxicity of a Pharmacologically Active Group of ortho-(Arylalkynyl)phenoxypropanolamines

JAMES W. OLDHAM*, JOHN R. CARSON{dagger}, ALAN GILL{ddagger}, ROBERT F. PRESTON* and DEBRA D. SEDOR*

*Department of Toxicology, R. W. Johnson Pharmaceutical Research Institute at McNeil Pharmaceutical Spring House, Pennsylvania 19477 {dagger}Departments of Chemical Research, Janssen Research Foundation Spring House, Pennsylvania 19477 {ddagger}Departments of Biological Research, Janssen Research Foundation Spring House, Pennsylvania 19477

Received June 29, 1989; accepted September 14, 1989

Genetic Toxicity of a Pharmacologically Active Group of ortho-(Arylalkynyl)phenoxypropa-nolamines. OLDHAM, J. W., CARSON, J. R., GILL, A., PRESTON, R. F., AND SEDOR, D. D. (1990). Fundam. Appl. Toxicol. 14, 376–385. A series of ortho-(arylalkynyl)phenoxypropa-nolamines with antihypertensive activity in laboratory animals was screened in vitro for mutage-nicity using the Ames test and the mouse lymphoma assay, and for DNA damaging potential in the primary rat hepatocyte/DNA repair assay. Those compounds with a dialkylamino group on the para position of the arylalkynyl function were shown to be genotoxic in both mutagenicity assays when tested in the presence of an Aroclor 1254-induced rat liver S-9 mix. They were also active in the DNA repair assay. Removal of the para-dialkylamino group or changing the position of this group on the aryl ring eliminated the genotoxic effect in these test systems. This collaborative effort between chemists, pharmacologists, and toxicologists successfully identified the structural feature responsible for the genotoxic activity and indicated structural alterations that would yield a pharmacologically active compound with no genotoxicity in these in vitro assays.


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