74P
QUANTITATIVE STRUCTURE-ACTIVITY STUDY OF INHIBITION OF BLOOD PLATELET AGGREGATION BY ASPIRIN DERIVATIVES J . C . Dearden, E . George, School of Pharmacy, Liverpool Polytechnic, Bwom S t r e e t , Liverpool L3 3AF, U.K.
The p l a t e l e t - a g g r e g a t i o n i n h i b i t o r y a b i l i t i e s of a s p i r i n and twerity-three rings u b s t i t u t e d d e r i v a t i v e s have been i n v e s t i g a t e d i n vivo i n t h e r a b b i t . Aggregation was examined i n t h e Bryston HU aggregometer, using r a b b i t tendon c o l l a g e n as aggregating a g e n t , a t one hour a f t e r o r a l dosing and a t maximal i n h i b i t i o n . L i p o p h i l i c i t i e s were determined chromatographically a t pH 1.1 on polyamide p l a t e s (Dearden, P a t e l & Tubby, 1974). I t was found t h a t t h e one-hour r e s u l t s could be f i t t e d reasonably well by a q u a d r a t i c equation:
- 28.767 RMf M n = 1 5 , r = 0.846, s = 0.227
log ( 1 / E D 5 0 ) = 3.565 - 9.063 R
I n c l u s i o n of e l e c t r o n i c and s t e r i c terms d i d not improve t h e c o r r e l a t i o n . mose compounds with log P values above about 2.5 showed no d e t e c t a b l e i n h i b i t o r y a c t i v i t y a f t e r one hour. Maximal i n h i b i t i o n was i n v e s t i g a t e d i n order t o t e s t t h e computer model p r e d i c t i o n (Dearden & Townend, 1976) t h a t maximal potency should approach a maximum asymptotically a s l i p o p h i l i c i t y i n c r e a s e s . I t was found t h a t t h e i n h i b i t o r y e f f e c t increased t o a maximum and then f e l l s l i g h t l y a s l i p o p h i l i c i t y i n c r e a s e d . “his f a l l may be caused by one o r more of a number of f a c t o r s : ( i )increased metabolism with i n c r e a s e d i n vivo residence t i m e ; we have found t h a t s a l i c y l i c a c i d i s about lo00 times l e s s a c t i v e than i s a s p i r i n i n i n h i b i t i n g p l a t e l e t aggregation; ( i i ) competition of t h e corresponding s a l i c y l i c a c i d f o r t h e binding s i t e ; we have found t h a t t h e more l i p o p h i l i c t h e s a l i c y l i c a c i d d e r i v a t i v e , t h e more e f f e c t i v e l y does i t prevent a s p i r i n from i n h i b i t i n g p l a t e l e t aggregation ( c f . L e f o r t & Vargaftig, 1977); (iii)poor aqueous s o l u b i l i t y of t h e more l i p o p h i l i c d e r i v a t i v e s ( c f . Flynn & Yalkowsky, 1972); ( i v ) p r e f e r e n t i a l s t o r a g e of l i p o p h i l i c d e r i v a t i v e s i n adipose t i s s u e . Dearden, J . C . , P a t e l , A.M. & Tubby, J . H . (1974). J . Pharm. Pharmac., 26, Suppl., 74P-75P. Dearden, J.C. & Townend, M.S. (1976). I b i d , 28, Suppl., 13P. Flynn, G.L. & Yalkowsky, S . H . (1972). J. Pharm. S c i . , 61, 838-852. L e f o r t , J . & Vargaftig, B.B. (1977). B r i t . J . Pharmacol., 60, 292P-293P.
QUANTITATIVE STRUCTURE-ACTIVITY STUDY OF INHIBITION OF BLOOD PLATELET AGGREGATION BY ASPIRIN DERIVATIVES J . C . Dearden, E . George, School of Pharmacy, Liverpool Polytechnic, Bwom S t r e e t , Liverpool L3 3AF, U.K.
The p l a t e l e t - a g g r e g a t i o n i n h i b i t o r y a b i l i t i e s of a s p i r i n and twerity-three rings u b s t i t u t e d d e r i v a t i v e s have been i n v e s t i g a t e d i n vivo i n t h e r a b b i t . Aggregation was examined i n t h e Bryston HU aggregometer, using r a b b i t tendon c o l l a g e n as aggregating a g e n t , a t one hour a f t e r o r a l dosing and a t maximal i n h i b i t i o n . L i p o p h i l i c i t i e s were determined chromatographically a t pH 1.1 on polyamide p l a t e s (Dearden, P a t e l & Tubby, 1974). I t was found t h a t t h e one-hour r e s u l t s could be f i t t e d reasonably well by a q u a d r a t i c equation:
- 28.767 RMf M n = 1 5 , r = 0.846, s = 0.227
log ( 1 / E D 5 0 ) = 3.565 - 9.063 R
I n c l u s i o n of e l e c t r o n i c and s t e r i c terms d i d not improve t h e c o r r e l a t i o n . mose compounds with log P values above about 2.5 showed no d e t e c t a b l e i n h i b i t o r y a c t i v i t y a f t e r one hour. Maximal i n h i b i t i o n was i n v e s t i g a t e d i n order t o t e s t t h e computer model p r e d i c t i o n (Dearden & Townend, 1976) t h a t maximal potency should approach a maximum asymptotically a s l i p o p h i l i c i t y i n c r e a s e s . I t was found t h a t t h e i n h i b i t o r y e f f e c t increased t o a maximum and then f e l l s l i g h t l y a s l i p o p h i l i c i t y i n c r e a s e d . “his f a l l may be caused by one o r more of a number of f a c t o r s : ( i )increased metabolism with i n c r e a s e d i n vivo residence t i m e ; we have found t h a t s a l i c y l i c a c i d i s about lo00 times l e s s a c t i v e than i s a s p i r i n i n i n h i b i t i n g p l a t e l e t aggregation; ( i i ) competition of t h e corresponding s a l i c y l i c a c i d f o r t h e binding s i t e ; we have found t h a t t h e more l i p o p h i l i c t h e s a l i c y l i c a c i d d e r i v a t i v e , t h e more e f f e c t i v e l y does i t prevent a s p i r i n from i n h i b i t i n g p l a t e l e t aggregation ( c f . L e f o r t & Vargaftig, 1977); (iii)poor aqueous s o l u b i l i t y of t h e more l i p o p h i l i c d e r i v a t i v e s ( c f . Flynn & Yalkowsky, 1972); ( i v ) p r e f e r e n t i a l s t o r a g e of l i p o p h i l i c d e r i v a t i v e s i n adipose t i s s u e . Dearden, J . C . , P a t e l , A.M. & Tubby, J . H . (1974). J . Pharm. Pharmac., 26, Suppl., 74P-75P. Dearden, J.C. & Townend, M.S. (1976). I b i d , 28, Suppl., 13P. Flynn, G.L. & Yalkowsky, S . H . (1972). J. Pharm. S c i . , 61, 838-852. L e f o r t , J . & Vargaftig, B.B. (1977). B r i t . J . Pharmacol., 60, 292P-293P.
