Discovery of 1,5-Benzodiazepines with Peripheral Cholecystokinin (CCK-A) Receptor Agonist Activity (II):  Optimization of the C3 Amino Substituent

Abstract

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.

Molecular Basis for Benzodiazepine Agonist Action at the Type 1 Cholecystokinin Receptor

“…This ligand has unique characteristics, acting as a specific agonist for type 1 CCK receptors (CCK1R) and an antagonist for type 2 CCK receptors (CCK2R) (4,5,8). Radioiodinated 1,4-benzodiazepine ligands for the type 1 and type 2 CCK receptors were prepared by oxidative radioiodination using IODO-BEADs, and purifying the product to homogeneity with a specific radioactivity of ϳ2000 Ci/mmol on reversed-phase HPLC, as described previously (9).…”

“…A key molecule used in these studies was the 1,5-benzodiazepine developed at GlaxoSmithKline Research Laboratories, GI181771X, which has a unique functional profile, being a type 1 CCK receptor agonist and a type 2 CCK receptor antagonist (4,5). This provided an ideal ligand to study binding and activation mechanisms of the two closely related CCK receptors.…”

Analysis of the anorectic efficacy of HMR1426 in rodents and its effects on gastric emptying in rats

“…21,22 Since the discovery of two subtypes of CCK receptors, CCK A receptors predominantly located in the periphery and the CCK B receptor located in the CNS, 23 numerous nonpeptidergic CCK A agonists have been synthesized and have been shown to mimic all properties of CCK. [24][25][26] We therefore tested whether HMR1426 was acting as a CCK A agonist. The CCK A agonist GW5824 inhibited cumulative milk consumption in mice after 2, 4 and 6 h on an average by 98%.…”

Radiosynthesis of carbon‐11‐labelled GI181771, a new selective CCK‐A agonist

“…Analytical data were in accordance with the structure: (R,S)-11 and GW502085X: (S)-11) were available at GlaxoSmithKline and prepared according to Reference. 6 Analytical methods. HPLCs were performed on Waters or Shimadzu systems.…”

“…4,5 Among a series of 1,5-benzodiazepine selective CCK-A receptor agonists, GI181771, namely (S)-3-(3-f1-[(isopropylphenylcarbamoyl)methyl]-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[b] [1,4]diazepin-3-ylgureido)benzoic acid ((S)-1, Figure 1), has been identified as an orally active satiety agent in a rat-feeding model. 6 Positron emission tomography (PET) is a high-resolution, sensitive, molecular and functional imaging technique, which permits repeated, noninvasive assessment and quantification of specific biological and pharmacological processes. It is also the most advanced technology currently available for studying in vivo molecular interactions and plays an increasing role in both drug discovery and development of pharmaceuticals, by assessing their in vivo distribution, pharmacokinetics and dynamics.…”