| Autor: |
Hirst, G. C., Aquino, C., Birkemo, L., Croom, D. K., Dezube, M., Dougherty, R. W., Jr., 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. |
| Zdroj: |
Journal of Medicinal Chemistry; December 20, 1996, Vol. 39 Issue: 26 p5236-5245, 10p |
| Abstrakt: |
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. |
| Databáze: |
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