Analogs of the previously reported 1,5-benzodiazepine peripheral cholecystokinin (CCK-A) receptor agonist 1 were prepared which explore substitution and/or replacement of the C-3 phenyl urea moiety. Agonist efficacy on the isolated guinea pig gallbladder (GPGB) was retained with a variety of substituted ureas and amide analogs. Three compounds were identified which were orally active in the mouse gallbladder emptying assay (MGBE). The 2-indolamide (52) and N-(carboxymethyl)-2-indolamide (54) derivatives had improved affinity for the human CCK-A receptor but reduced agonist efficacy on the GPGB. Neither indolamide was orally active in a rat feeding assay. In contrast, the (3-carboxyphenyl)urea derivative (29, GW7854) had moderately increased affinity for the human CCK-B receptor but was a potent full agonist on the GPGB and was orally active in both the MGBE and rat feeding assays. GW7854 was a full agonist (EC50 = 60 nM) for calcium mobilization on CHO K1 cells expressing hCCK-A receptors and a potent antagonist of CCK-8 (pA2 = 9.1) on CHO K1 cells expressing hCCK-B receptors. GW7854 is a potent mixed CCK-A agonist/CCK-B antagonist which is orally active in two in vivo models of CCK-A-mediated agonist activity.

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Discovery of 1,5-Benzodiazepines with Peripheral Cholecystokinin (CCK-A) Receptor Agonist Activity (II): Optimization of the C3 Amino Substituent.-The synthesis and biological profile of analogues of (VIIa) are reported which explore both substitution and/or replacement of the C-3-position phenyl urea moiety. The goal is to identify compounds which are orally active agents in a rat feeding model. The derivatives (VIIb) and (VIId) are potent, fully efficacious and orally active in the mouse gallbladder emptying assay. (VIIb) is a potent mixed CCK-A agonist/CCK-B antagonist which is orally active in two in vivo models of CCK-A mediated agonist activity. -(HIRST, G. C.; AQUINO, C.; BIRKEMO, L.; CROOM, D. K.; DEZUBE, M.; DOUGHERTY, R. W. JUN.; ERVIN, G. N.; GRIZZLE, M. K.; HENKE, B.; JAMES, M. K.; JOHNSON, M. F.; MOMTAHEN, T.; QUEEN, K. L.; SHERRILL, R. G.; SZEWCZYK, J.; WILLSON, T. M.; SUGG, E. E.; J. Med.