868 Journcti of h'edicinal Chemistry, 1871, vel. 14, lye. 9
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Biologically Oriented Organic Sulfur Chemistry. 8. Structure-Activity Relatioiiships of Penicillamine Analogs and Derivatives' B. J. SWEETMAN, AI. AI. VESTLING,S. T. TICARIC, 1'. I,. KELLY,I,. Department of Chemistry, Vanderbzlt L'nzverszty, Sashville, Tendessee
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P. MERRYMAN, AND I. A. JAFFE Department of Medzcine, -Yew York Medzcal College, A'ew Y o r k , ,Yew York
10029
Received November IS, 1970
D-Penicillamine (1) is of interest for the treatment of rheumatoid arthritis, but it, causes many side effects. Evaluation of substances structurally related to 1 was made for effectiveness in reducing the tensile strength of rat skin in civo, a parameter of 1 significant to collagen biochemistry, if not to rheumatoid arthrit,is. The moieties SH, "2, and COtH all appeared to be necessary for reduction of tensile strength, for activity was lacking whenever any one of them was omitted or was blocked by substitution. Variations of the skeleton are possible, since a-amino-0-mercaptocyclohexaneacetic acideHC1 (13) is a t least as active as 1. Latentiation of I and related compds led to one product (17), contg an S-(0-carboxyphenylthio) moiety, which had activity comparable t o 1. Slight activity was seen for the Me ester of 1 and for a-mercaptopropionylglycine. Indications are that 1 may owe its effect in rheumatoid arthritis to something other than to dissociation of the rheumatoid factor, to function as an antiinflammatory or immunosuppressive agent, or to strengthening of a lysosomal membrane.
D-Penicillamine (1) is of interest in treating a wide this characterist,ic has been suggested as a possible exvariety of illnesses, e.g. , Wilson's Disease,2 cystinuria, planation for the effect of 1 in solubilizing collagen, a idiopathic pulmonary f i b r ~ s i s ,rheumatoid ~ a r t h r i t i ~ , ~ principal protein constituent of connect,ive tissue, and and scleroderma.'j Significant clinical improvement in markedly reducing the tensile strength of skin in rats.I3 Whether or not these effects of 1 on collagen (CH,)?C(SH)CH(NH, )C02H and skin are relevant to diseases of connective tissue is 1 uncertain, but' a t the time we began our investigation, 1 in a number of patients having rheumatoid arthritis was the only compound known to have such effects iii has been attributed to prolonged oral administration of vivo. 1 ,5 but t'he clinical usefulness of 1 is limited by many side This paper reports the results of several biological effects, among which renal damage is particularly tests carried out on 1 and on a series of analogs and detroublesome.' rivatives of l in a search for other substances of The mechanism by which 1 acts in rheumatoid potential int'erest in diseases of connect,ive tissue. arthritis is not clear. Chemically, 1 is ltnow*n to cheFor synthesis of compounds related tto 1 t'hat would late heavy metals8 and to effect thiol-disulfide interbe more active medicinally and/or less toxic, 3 apchange to some extent ;9 indeed, its chelat'ion capability proaches suggested themselves : (1) determination of is important), for example, in the treatment of P b the funct'ional groups and skeletal features of 1 that are poisoning.'O However, neit,her chelation nor thiolrequired for action on connective tissue; clarification of disulfide int'erchange seems likely t o explain the effect' this point hopefully may lead also to a clearer view of of 1 in rheumatoid arthritis." On the other hand, 1 the mechanism of action of 1 in diseases of connective forms thiazolidines with aldehydes or and t'issue; (2) investigation of latentiating moieties14 for 1 in the hope of obtaining pharmacologically more useful (1) (a) Paper 7 , L. Field, JV. S. Hanley, 1. McVeigh, and Z. Evans, J . compounds from 1 ; (3) coupling of molecules emM e d . C h e m . , 14, 202 (1971). ( b j This investigation was supported by Public Health Service Research Grant AM11685 from the National Institute of bodying the best structural parameters with t'he most -4rthritis and Metabolic Diseases t o Vanderbilt University and b y Contract promising latentiating moieties. K O ,DA-49-193-MD-2445 from the U. S. Army Medical Research and DeBiological Results.-Rheumatoid arthrit>isis one of' velopment Command and Public Wealth Service Research Grant AM11586 from the National Institute of Arthritis and hletabolio Diseases t o N e v the rheumatic diseases that include diseases of conTork Medical College. nective tissue.15 Although it may be coincidental that (2) (a) J . M , Walshe, Lancet, i, 188 (1960); (h) I. Sternlieb and I. €I. Scheinberg, J . A m e r . M e d . A s s . , 189, 748 (1964). 1 has a favorable influence in rheumatoid arthritis and (3) (a) J. C . Crawhall, E. F. Scowen, and R . TV. E. Watts, B r i t . Med. J . , that' it also reduces the t,ensile strength of rat skin in. 1, 588 ( 1 9 6 3 ) ; (b) €1. Rostrom and P. 0. Wester, A c t a M e d . S c a n d . , 181, 475 vit'013 and in vitro,'G the most attractive means (at least' (1967). (4) Cf. R . I. Henkin, H. R . Keiser, I . A . Jaffe, I. Sternlieb, and I. H . in the present state of knowledge) for studying the Scheinberg, Lancet, ii, 1268 (1967). structural features of 1 likely t,o be important in ar( 5 ) I. A . Jaffe, Postgrad. .Wed. J . , Oct. S u p p l . , 44, 34 (1968). thritis seemed to be to follow the effect of structural ( 6 ) E . D . Harris, J r . , and A . Sjoerdsma, Lancet, ii, 996 (1966). (7) C/. I . A . Jaffe, G. Treser, Y . Suzuki, and T . Ehrenreich, Ann. I n t e r n . variations of 1 on the capacity for reducing the tensile M e d . , 69, 549 (1968). strength of rat skin in vivo. I n view of widespread ( 8 ) A I . L. Sharma and L. D. Tuck, 158th National Meeting of t h e American Chemical Society, New York. N. Y., Sept 1969, MEDI 59. interest in the biochemistry of collagen, such results ( 9 ) L. Eldjarn and L. Hambraeus, S c a n d . J . Clin. L a b . Invest., 18, 153 (1964). (10) W. G. Levine in "The Pharmacological Basis of Therapeutics," L. S. Goodman and A . Oilman, E d . , 3rd ed, Macmillan Co., New York, A'. Y . , 1965, p 939. ( 1 1 ) I . A . Jaffe, A r t h r i t i s Rheum., 8, 1064 (1965). ( 1 2 ) .IET. . Cook and I. h l . Heilbron in "The Chemistry of Penicillin," H . T . Clarke, J. R . Johnson, and R . Robinson, E d . , Princeton University Press, Princeton, K .J.. 1949, p 921.
(13) (a) >I. E. Kimni, J . Biol. C h e m . , 243, 1457 (1968); ( h j I
