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Br. J. clin. Pharmac. (1982), 13, 331-339 RELATIVE POTENCY AND STRUCTURE ACTIVITY RELATION- SHIPS OF ALDOSTERONE ANTAGONISTS IN HEALTHY MAN: CORRELATION WITH ANIMAL EXPERIENCE G.T. McINNES, J.R. SHELTON, L.E. RAMSAY, I.R. HARRISON, M.J. ASBURY, J.M. CLARKE, R.M. PERKINS & G.R. VENNING Division of Clinical Research, G.D. Searle & Co. Ltd, Lane End Road, High Wycome, Bucks HP12 4HL 1 The renal antimineralocorticoid potency of single doses of thirteen compounds with properties in animals compatible with competitive aldosterone antagonism was compared to that of spirono- lactone in healthy men. 2 Twelve compounds showed significant activity when compared to placebo but only one, pro- renoate potassium, was significantly more potent than spironolactone on a weight basis. 3 The results allowed ranking of the compounds in order of potency relative to spironolactone and general observations on structure activity relationships in man. 4 Animal bioassays and in vitro aldosterone binding studies are unreliable predictors of the human activity of competitive mineralocorticoid antagonists. Introduction Spironolactone is a competitive aldosterone an- Mclnnes et al. (1980) which in turn evolved from tagonist (Kagawa, 1960a; Drill, 1962) which is used in earlier work by Ross (1962), who showed that single the treatment of hypertension and in conditions doses of the orally active synthetic mineralocorticoid, where there is salt and water retention (Ochs et al., fludrocortisone, given in the evening, consistently 1978). Since its introduction numerous related struc- depressed the ratio of sodium to potassium in the tures have been synthesised and their renal anti- overnight urine of normal men with a dose-response mineralocorticoid activity has been studied in animals. which exhibited parallelism with that of aldosterone. However, few compounds have been assessed in man. The ratio returned towards normal in the presence of Thus the hypothesis that the potency of a competitive competitive mineralocorticoid antagonists by virtue mineralocorticoid antagonist in animal laboratory of an increase in sodium excretion and a decrease in screening reflects its potency in human subjects is potassium excretion. Use of these parameters and largely untested. functions of them allows comparison of the activity For two compounds, canrenoate potassium and of mineralocorticoid antagonists and an estimate of prorenoate potassium, studies in rats and dogs did not their potency relative to a standard, spironolactone. predict reliably the potency observed in healthy man (Ramsay et al., 1975a, 1976). We have now examined Study designs by standardised methods in healthy men, the pharma- cological activity of 13 structures related to spirono- The experiments were carried out according to lactone and showing antimineralocorticoid activity in double-blind, randomised, balanced crossover animals. We use these-data to explore structure activity designs. Eleven drugs were examined in three-phase relationships in man, and to determine the predictive studies, the treatments compared being new value of screening methods using laboratory animals, aldosterone antagonist, spironolactone and placebo. both in vivo and in vitro. Four were examined in six-phase studies, the treat- ments being the new aldosterone antagonist and spironolactone, each at three dose levels, the inten- Methods tion being to yield two drug, three dose parallel line bioassays in each instance. Two drugs were studied in The methods used in these studies closely followed both methods. The phases of the studies were those described by Ramsay et al. (1975a, 1976) and separated by 1 week intervals. 0306-5251/82/030331-09 $01.00 (©) Macmillan Publishers Ltd 1982 332 G.T. McINNES ETAL. Subjects Six-phase studies A total of 114 male subjects considered to be healthy 1. New aldosterone antagonist: after medical history, physical examination and (a) SC23992: 10 mg, 20 mg and 30 mg (10 mg laboratory screening, were studied, six or twelve tablets) plus placebo spironolactone volunteers taking part in each experiment. All forms (b) SC27169: 50 mg, 100 mg and 200 mg (50 or of medication were prohibited from 1 week before 100 mg chemical in opaque gelatin the studies until their completion. Salicylates were capsules) plus placebo spirono- specifically forbidden since they are known to inter- lactone fere with the urinary electrolyte response to spirono- (c) SC14266: 100 mg, 150 mg and 200 mg (in lactone (Tweeddale & Ogilvie, 1973). Alcohol was not 300 ml aqueous solution) allowed from 24 h before each medication until the (d) SC8109: 250 mg, 500 mg and 1000 mg urine collections were completed. (125 mg chemical in opaque gelatin capsules) plus placebo spirono- Procedure lactone 2. Spironolactone 25 mg, 50 mg and 100 mg* (25 mg Until 17.30 h on study days, the subjects continued tablets)t plus placebo new aldosterone antagonist normal activities and diet. At 19.00 h fludrocortisone *In study of SC23992: 75 mg was taken and in the next 30 min, a prescribed light tIn study of SC14266: spironolactone in 300 ml meal, identical on all occasions, was consumed. At aqueous suspension 21.00 h, the test medication was administered with a Fludrocortisone 0.5 mg (5 x 0.1 mg tablets)- volume of water constant within a given study and a SC23992 and SC8109 studies or 1 mg (1 x 1 mg further constant volume of water was taken at 23.00 tablets)-SC27169 and SC14266 studies. h. All urine passed between 23.00 h and 07.00 h the next day was collected. In the three-phase studies, a Laboratory further 0.5 mg fludrocortisone was taken immediately thereafter and the subjects ate a prescribed light Urine was collected without preservatives and after breakfast. Urine was again collected from 09.00 h measurement of volume, an aliquot was stored at until 13.00 h. This modification of the basic pro- -20°C. Urinary sodium and potassium concentra- cedure allows examination of the later phases of tions were measured by atomic absorption spectro- activity of the antagonists (McInnes et al., 1980; photometry. Samples were batched by study phase Ramsay et al., 1975a). Urine and venous blood for for laboratory analysis. Screening tests were by con- laboratory screening, including urinalysis, blood ventional laboratory procedures. urea, electrolytes, liver function tests and haema- tology, were sampled 12 h before and after each Statistical analysis medication and 1 week after completion of each study. All screening was at 09.00 h to avoid possible The statistical methods employed are described by effects of diurnal variation. General enquiry for Armitage (1973). The antagonist treatment effects possible side effects was made 12 h and 1 week after were compared by analysis of variance, allowing for each treatment. subject and phase effects in the linear model. Logarithmic transformation was performed to Drugs stabilise the variance of the ratio variable (10 x Na/K) and hence validate the analysis of variance, The compounds studied were spirolactones or with the additional advantage of linearising the dose- closely related soluble potassium salts of steroid acids response relationship. (Figure 1). Full chemical names are given in the In the three-phase experiments, where there was Appendix. an overall difference between the treatments, the Newman-Keuls (Studentized Range) multiple com- Three-phase studies parison technique was used to test: 1. Activity of new aldosterone antagonist (v placebo). 1. New aldosterone antagonist, 50 mg chemical in 2. Activity of spironolactone (v placebo). an opaque gelatin capsule plus placebo spirono- 3. New aldosterone antagonist v spironolactone. lactone. In the 2-10 h collection, the slope of the log spirono- 2. Spironolactone, 50 mg (2 x 25 mg Aldactone lactone dose-log,() 10 Na/K response relationship tablets) plus placebo capsule. derived from previous studies was used to estimate 3. Double placebo the potency of each new aldosterone antagonist rela- Fludrocortisone (Florinef, Squibb), 0.5 mg (5 x tive to spironolactone, with 95% confidence limits. 0.1 mg tablets) at 19.00 h and 07.00 h the next day. This estimation requires the assumptions of a linear ACTIVITY OF ALDOSTERONE ANTAGONISTS IN HEALTHY MAN 333 a) L) a) 0 LA C)I) 0 8E i~~ o~~~~~~~~8 .5. '12; ~0 8 0 U a co oo y) ~~~~~~~~C,, CLQ 0 0 D) C/, .0 W C Q 4._ ICl) ax u 0 ca 0 C) 0.) C 1- Coo CZ \/--0 CY)c0 -o S- \/7 e u ._ 0 < OD C0 Cn CD) ~~I 0 0) Cl) 'D ' C 1- n 0 8 0 C2U) Ul) - C. VN 0 0 -. (N .0 oLO I 334 G.T. McINNES ETAL. log dose-response relationship for the new aldosterone relative to spironolactone Using urinary log,( 10 Na/K antagonist, which is not unreasonable in the presence in the 2-10 h collection as response, the potency of of significant activity compared with placebo, and the test drugs relative to spironolactone, with 95% parallelism with the spironolactone relationship. This confidence limits, were calculated from the data approach has been described in detail (McInnes et al., presented in Table 1. The estimates are shown in 1981a). Table 2. The potency estimates ranged from 1.10 to In the six-phase studies, the significance of the 0.20. Four of the compounds SC25951, SC26714, linear log dose-log,(1 10 Na/K response trends for the SC27169 and SC28947 had potency not significantly new aldosterone antagonists and spironolactone were different from that of spironolactone (confidence tested and their slopes compared. Provided the slopes limits bracketed unity) but the remaining seven were significant and there was not significant contra- agents were significantly less potent than spirono- indication to either linearity of parallelism, the lactone and indeed SC28666 had no demonstrable validity of the parallel line bioassay was accepted and antimineralocorticoid activity in this model. the potency of the new aldosterone antagonists relative to spironolactone were estimated with 95% confidence limits.