FORSCHUNG 338 CI·IIMIA 46 (1992) Nr. 7/8 (Juli/Augusl) Chimia 46 (1992) 338-344 Some fifteen years ago, we have de- © Neue Schweizerische Chemische Gesellschaft cided to try to use a rational [9] approach ISSN 0009-4293 to the development of a 'superstrong' DC for an effective treatment of obstinate dermatoses which do not respond to the treatment with strong compounds, e.g. betamethasone valerate. Concept and Development Besides the classical antiinflammato- ry tests, like e.g. Tonelli's 'rat-ear-derma- of a Potent Topical titis-inhibition test' [10], a high activity of the test compounds in one of the most Corticosteroid [1][2] relevant dermato-phannacological assays - the McKenzie's 'human-skin vasocon- triction test' [11] - in a version developed in our laboratories (the HVK test) [8] was Jaroslav Kalvoda* [3][4], Jiirgen Grob [4], Klaus Jakel [5], Rene Maier [4], chosen for the characterization of DC's as Peter Moser* [5], Hermann Fuhrer [5], Erich G.Weirich [4][6], and Shantaram the primary selection criteria. J. Yawalkar [7] It has been shown in many reports about percutaneous resorption that the Ahstract. In a rational approach to identify an ultrapotent compound for the treatment flux, I, of a compound completely dis- of therapy-resistant dermatoses, Weirich's modification [8] of McKenzie's skin vaso- solved in a vehicle, through the skin is constriction assay (HVK test) has been used as the essential selection criteria. In a strongly dependent on its lipophilicity. primary phase, a quantitative relationship between the HVK activity of 25 derivatives According to Scheuplein [12], this fact of corticosterone substituted in various positions of the skeleton, and their lipophilicity can be mathematically expressed by the (log P) was established. The specific lipophilicity-independent interactions were following equation: accounted for by the inclusion of 'indicator variables' into the regression analysis. The Pm . Dm . L1(Cs) highly significant results allowed to localize an optimal log P range and to identify the I = dQ/dt = influence of various substituents. In a next phase, the evidence of the firstHVK analysis d was refined by considering 28 additional compounds. On the basis of the confirmed Pm = partitIOn coefficient stratum facts, six 21-chloro-6a-fluoro compounds were specifically synthesized and submitted corneum/vehicle to dermatopharmacological testing. Finally, CGP 14458 (= 2l-chloro-6a,9-difluoro- Dm = diffusion coefficient in stratum \1,B-hydroxy-16,B-methyl-3,20-dioxopregna-l ,4-dien-17 a-yl propionate) which was corneum predicted to be the most potent representative of these series, whose synthesis is L1(Cs)= difference in concentration described in detail, showed indeed to be the most effective compound. Clinical trials through the stratum corneum with this compound - halobetasol propionate/Ultravate® (ulobetasol/Miracorten®) - d = diameter of the stratum cor- confirmed its unique efficacy, especially in the treatment of severe, chronic plaque neum psoflasls. General 21 OR1 21 X The corticosteroid hormones produced o by the adrenals, as well as their more potent synthetic analogues, are represent- ing a type of compounds of vital impor- Q tance to men, showing a very broad spec- trum of activity. o During the past decades, beside the ;6 Y classical systemic application of gluco- corticosteroids, which, in spite of the great Series: HYDROCORTISONE Series: DEXA-I FLUMETHASONE popularity ofNSAID's, is still considered to be the essential treatment of many life- threatening diseases, there have been in- 21 OR troduced into therapy the so-called derma- 21 X tocorticoids (DC). Their use for the topi- o cal treatment of skin allergies, inflamma- tions, and proliferating dermatoses of the human skin has become indispensable. o ~6 o Y Series: TRIAMCINOLONE I Series: BETAMETHASONE Correspondence: Dr. J. KalvodalDr. P. Moser FLUOCINOLONE Ciha-Geigy AG [Q, Y, Z = H, Hal; X = CI, OAe, OH; R, Rl' R2 = H, Ae; R1+A1 = C(CH3)2] K-136.P21jK-24.U.103 CH-4002 Basel FORSCHUNG 339 CHI MIA 46 (1992) Nr. 7/8 (JlIli/AlI~usl) In a steady state, the amount of the compound transported per time unit log Wrel through the skin is proportional to the 3.0 - partition coefficient between the vehicle • and the stratum corneum. .,,-,--- .--.---- 2.5 " We have, therefore, decided to try to ,,,' . deduce in the first part of our study a . ,,//: ~. quantitative correlation between the HVK 2.0 .~ ~. // .. activity of the test compounds and their ,,". lipophilicity expressed as partition coeffi- 1.5 ., "" cients in the system octanol1H 0, which is " 2 " believed to mimic the in vivo situation .." 1.0 ,I" best. I I For the first step of our investigation, I I I we have selected a series of 25 steroids 0.5 / I belonging to four different groups of DC ' s, 1 Fig. I. 1st HVK Test namely, those of hydrocortisone (HC), / . o I (human skin \'asocon- dexamethasonelflumethasone, triamci- I. strictio11assay). DMWDIIC nolonelfluocinolone and betamethasone. Iog Wrei = Iog DMV,ib= The lipophilicity has been manipulated 1.0 2D 3.0 4.0 log P -2.79 + 2.36 log P mainly by variation of the substituents in -0.28 (log P)2; 11 = 25, positions 2, 9, and 21 ofthe steroid nucle- I' = 0.862, s = 0.470. us. In (Figs. 1-4), the logarithms of the relative potencies, log Wrei' are plotted against the log P values of the compounds. log Wrel In spite of the relative large deviations of 3.0 the single points from the parabola calcu- lated by multiple regression, a clear-cut dependence is observed between the vaso- constrictor activity and the log P value. In 2.0 addition, a presumably optimal log P area can be observed in the range of about 3.5- 4.5. The next step consisted in a refinement 1.0 of the regression by inclusion of indicator variables in the so-called mixed Hansch- Free- Wilson approach [13]. Indicator var- Fig. 2.1 st HVKTest. Com- puted values corrected by iab~es, X .' are discrete variables which 0.0 ij the increments of the sub- can assume the value of either 0 or 1, stituents deduced from describing thereby the presence or ab- mixed analysis. log W rei = sence of a specific substituent. The corre- -1.59 + 1.29 log P - 0.13 -1.0 (logP)2+0.70(6-F)+ 1-02 sponding coefficients, Aij, calculated by 1.0 2.0 3.0 multiple linear regression express the con- 4.0 5.0 log P (l6/i-CH3) + 0.42 (16,17- tributions of the particular substituents to Aeetonid); 11 = 25,1'=0.96, s = 0.306. the overall activity. By admixing the log P, a separation can be achieved between the Iipophilicity-dependent contributions and specific interactions of the substituents at synthesize new derivatives, whose vaso- clobetasol propionate (CGP 9'555), the the molecular level. In our specific analy- constrictor activity would be expected to active ingredient of Glaxo's Dermovate®' sis, it has been shown that only the 6a- be distinctly superiorto that of compounds The inclusion of indicator variables leads fluorine, the 16,B-Me group, and the 16,17- which we have already tested. Of special to the shown equation (Fig. 4) [14]. acetonide grouping give statistically sig- interest appeared to be the fact that a 6a- The correlation having an R value nificant contributions and have, therefore, F substituent having a strong positive ef- of 0.98 and a standard deviation of s = to be considered. fect upon the activity, showed no measur- 0.29 can be considered as highly satisfac- As is shown in Fig. 2, the standard able contribution to the lipophilicity. tory. deviation, after introducing the above dis- In the second analysis, there have been Below, there are reproduced the struc- cussed corrections, is clearly in the region included 28 additional compounds. As tures of the six already mentioned com- of the reproducibility of the biological mentioned before, particular attention has pounds showing a particularly high activ- data. This very positive result, combined been payed to the 6a-F compounds. ity in the HVK test and differing in respect with the relatively strict additivity of the The relative potencies, log W rei'shown to their configuration at C(l6), the substi- log P contributions of the individual sub- in Fig. 3 as a function of log P, are situated tution at C(2) and C(9) and in the number stituents on the steroid skeleton, and, there- in the expected range. The points carrying of C=C bonds. fore, with the calculability of the integral a CGP number correspond to six inten- They were subjected to an extended log P value of the compound, allowed us in tionally synthesized compounds and to secondary screening and compared with the second series of our experiments to the most active DC known up today - to each other in respect to activity and side FORSCHUNG 340 CHIMIA 46 (1992) Nr. 7/8 (Juli/AuguSl) effects. A synopsis of the results obtained activity is represented in this graph as a Beclomethasone [20] (1) appeared to in the 4 most important dermatophar- percentage of the factor 2000 x He. The be an ideal starting material for the planned macological tests [15] is presented in Fig. second parameter is a measure for the synthesis. The corresponding orthoester 2 5. intensity of the blanching reaction. generated 9p, 11-epoxide 3, which was The UV -dermatitis inhibition test in On the basis of these data and of the selectively hydrogenated in position 1(2) guinea pigs as well as the 'croton-oil- results of skin tolerability tests, CGP 14'458 under the known conditions of homoge- dermatitis-inhibition test' in rabbits do not (ulobetasol [l6]/Miracorten®; halobeta- neous catalysis in dioxane solution, to permit a clear differentiation of the com- sol propionate [17]/Ultravate® [18]) has yield the mono-unsaturated ketone 4.