Hirst G C, Aquino C, Birkemo L, Croom D K, Dezube M, Dougherty R W, 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
Department of Medicinal Chemistry, Glaxo Wellcome Research and Development, Research Triangle Park, North Carolina 27709, USA.
J Med Chem. 1996 Dec 20;39(26):5236-45. doi: 10.1021/jm9601664.
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.
制备了先前报道的1,5-苯二氮䓬外周胆囊收缩素（CCK-A）受体激动剂1的类似物，以探索C-3苯基脲部分的取代和/或替换。多种取代脲和酰胺类似物在分离的豚鼠胆囊（GPGB）上保留了激动剂效力。鉴定出三种在小鼠胆囊排空试验（MGBE）中具有口服活性的化合物。2-吲哚酰胺（52）和N-（羧甲基）-2-吲哚酰胺（54）衍生物对人CCK-A受体的亲和力有所提高，但对GPGB的激动剂效力降低。在大鼠进食试验中，这两种吲哚酰胺均无口服活性。相比之下，（3-羧基苯基）脲衍生物（29，GW7854）对人CCK-B受体的亲和力适度增加，但在GPGB上是强效的完全激动剂，并且在MGBE和大鼠进食试验中均具有口服活性。GW7854对于表达hCCK-A受体的CHO K1细胞上的钙动员是完全激动剂（EC50 = 60 nM），对于表达hCCK-B受体的CHO K1细胞上的CCK-8是强效拮抗剂（pA2 = 9.1）。GW7854是一种强效的CCK-A激动剂/CCK-B拮抗剂混合物，在CCK-A介导的激动剂活性的两种体内模型中具有口服活性。
