The effect of structural changes on the intramolecular degradation of the ‘dipeptoid’ CI-988

Abstract

CI-988 ([ R-(R∗,R∗)]-4-[[2-[[3-(1H-indol-3-yl)-2- methyl-1- oxo-2-[[( tricyclo[3.3.1.1 3,7] dec-2- yloxy )carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxobutanoic acid) is a selective, ‘dipeptoid’, cholecystokinin B receptor antagonist. To further investigate its mechanisms of degradation (i.e., apparent carboxyl-assisted amide-bond cleavage in acidic pH and hydroxide-ion catalyzed hydantoin formation in basic pH (Kearney et al., Pharm. Res., 9 (1992) 1095–1098), the kinetics of decomposition of three analogues of CI-988, differing only in the structure of the oxobutanoic acid side chain, were studied as a function of pH: I, [ R-(R∗,R∗)]-2-[[[2-[[3-(1 H-indol-3-yl)-2- methyl-1-oxo-2-[[( tricyclo[3.3.1.1 3,7] dec-2- yloxy) carbonyl]amino]propyl]amino]-1- phenylethyl]amino]carbonyl ]benzoic acid); II, R-(R∗,R∗)]-5-[[2-[[3-(1 H-indol-3- yl)-2- methyl-1- oxo-2-[[( tricyclo[3.3.1.1 3,7] dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-5-oxopentanoic acid); and III, [ R-(R∗,R∗)]-[2-[(2- ammo-2- phenylethyl) amino]-1-(1 H-indol-3- ylmethyl)-1- methyl-2- oxoethyl]carbamic acid tricyclo[3.3.1.1 3,7]dec-2-yl ester. Alterations to this oxobutanoic acid side chain had little to no effect on the hydroxide-ion catalyzed pathway supporting a common degradation mechanism for all of the compounds. One exception was when III had a positive charge on the terminal amino; the cationic species degraded about 250-times faster than CI-988, I, II, or the corresponding neutral species of III. Alterations to the side chain had a dramatic effect on the carboxyl-assisted pathway: I degraded about 100-times faster than CI-988 via an entropically driven reaction, whereas II degraded about 17-times slower than CI-988 (although a different degradation mechanism(s) was involved). As expected, these latter results indicate that the rate of intramolecular reaction between the carboxyl and amide groups depends on the flexibility and length of the intervening carbon chain.