Synthesis and pharmacological properties of "soft drug" derivatives related to perhexiline.
In the hope of reducing the toxicity of perhexiline, a series of 27 cyclohexylaralkylamines II based on the "soft drug" concept and incorporating an amide function were synthesized. In a preliminary screening, compounds were evaluated for their alpha-adrenolytic activities. Several derivatives, especially N-(cyclohexylphenylmethyl)-2-(cyclohexyl-methylamino)acetamide (3), N-(cyclohexylphenylmethyl)-2-(homoveratrylmethylamino)acetam ide (7), and N-[2-(cyclohexylamino)ethyl]-alpha-cyclohexylbenzeneacetamide (23) had the same activity range as perhexiline in vitro in rat aorta strips. The in vitro metabolism of these three molecules was then investigated and compared to that of perhexiline. The effect upon the alpha-adrenolytic activity of introducing various N-aralkylamine groups on II was examined. Structure/activity relationships are discussed.
D000317:Adrenergic alpha-Antagonists / Q000378:metabolism; D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D001011:Aorta; D001682:Biological Availability; D055598:Chemical Phenomena; D002621:Chemistry; D002851:Chromatography, High Pressure Liquid; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D010480:Perhexiline / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
D000317:Adrenergic alpha-Antagonists; D000577:Amides; D010480:Perhexiline