STRUCTURE-ACTIVITY RELATIONSHIPS OF ANABOLIC STEROIDS: ROLE OF THE 19-METHYL GROUP

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Abstract
Anabolic agents are therapeutically effective in a variety of diseases, and dissociation of the anabolic from undesirable androgenic activity has been shown in several newer steroid derivatives. One such modification is removal of the C-19-methyl group producing 19-nor compounds. With adequate animal data now available, a critical comparative clinical study was essential for evaluating the applicability of these structure-activity relationships to man. Since in the animal studies 17[alpha]-ethyl-19-nortestosterone had optimal anabolic activity, all possible compounds with a two-carbon atom side-chain at the 17[alpha] -position were studied, viz, 17[alpha]-ethyl-, 17[alpha]-vinyl-, and 17[alpha]-ethynyl derivatives of the testosterone (19-methyl) and 19-nortestosterone series. Each 19-nor compound was compared with the analogous 19-methyl compound (the only structural difference between pair members being presence or absence of the 19-methyl group) and with 17[alpha]-methyltestosterone. Comparisons were made at two dosage levels in the same person. Subjects were normal young women maintained on constant diets in a metabolic ward. Urinary nitrogen, sodium and potassium, and body weight were measured daily. Compounds of the 19-methyl series were inactive at dosage levels of 100-200 mg. per day, orally. All 19-nor compounds were strongly active in producing nitrogen retention, showing anabolic activity equivalent to that of 17[alpha]-methyltestosterone by this assay procedure. The high clinical potency of 2 of these, 17[alpha]-vinyl- and 17a-ethynyl-19-nortestosterone, could not have been predicted, since they manifested very low activity in animal studies. The observations suggest certain general relationships between structure, anabolic and androgenic activities of steroids.