Rationally designed "dipeptoid" analogues of CCK. Acid mimics of the potent and selective non-peptide CCK-B receptor antagonist CI-988.
This paper outlines the synthesis of selected acid mimics of the non-peptide CCK-B selective antagonist CI-988, 1. CCK-B and CCK-A binding affinities of these analogues are described and their CCK-B affinity and selectivity rationalized by consideration of the pK(a) values, charge distribution, and geometry of the respective acid mimics. Several of the compounds have CCK-B binding affinities similar to the parent carboxylic acid 1 (CCK-B, IC50 = 1.7 nM; pK(a) = 5.6) and span a pK(a) range of less than 1 (sulfonic acid 27) to greater than 9.5 (5-thio-1,2,4-triazole 24). Among the more active compounds synthesized are tricyclo[3.3.1.1(3,7)]dec-2-yl [R-(R*,R*)]-[2-[[2-[[(3-hydroxy-5-isoxazolyl)acetyl]-amino]-2- phenylethyl]amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl+ ++]carbamate (15), tricyclo[3.3.1.1(3,7)]dec-2-yl [R-(R*,R*)]-[1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[[2-[(1-oxo- 3-sulfopropyl)amino]-2-phenylethyl]amino]-ethyl]carbamate, monosodium salt (27), and tricyclo[3.3.1.1(3,7)]dec-2-yl [R-(R*,R*)]-[1-(1H-indol-3-ylmethyl)-1- methyl-2-oxo-2-[[2-[[(1H-1,2,4-triazol-5-ylsulfinyl)acetyl]a mino]-2-phenylethyl]amino]ethyl]carbamic acid (34) which have CCK-B binding affinities of IC50 = 2.6, 1.3, and 1.7 nM, CCK-A/-B ratios of 650, 780, and 550 and pK(a) values of 6.5, less than 1, and 7.0, respectively.
Drysdale
M J
MJ
Parke-Davis Neuroscience Research Centre, Addenbrookes Hospital Site, Cambridge, U.K.
Pritchard
M C
MC
Horwell
D C
DC
D000818:Animals; D002264:Carboxylic Acids / Q000737:chemistry; D002766:Cholecystokinin / Q000031:analogs & derivatives* / Q000494:pharmacology; D004151:Dipeptides / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D008536:Meglumine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D051381:Rats; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*
D002264:Carboxylic Acids; D004151:Dipeptides; D007211:Indoles; D011949:Receptors, Cholecystokinin; C065599:PD 134308; D008536:Meglumine; D002766:Cholecystokinin