Optimization of 1,3,4-Benzotriazepine-Based CCK₂ Antagonists to Obtain Potent, Orally Active Inhibitors of Gastrin-Mediated Gastric Acid Secretion

Abstract

Starting from a novel, achiral 1,3,4-benzotriazepine-based CCK2 receptor antagonist, a process of optimization has afforded further compounds of this type that maintain the nanomolar affinity for recombinant, human CCK2 receptors and high selectivity over CCK1 receptors observed in the initial lead but display more potent inhibition of pentagastrin-stimulated gastric acid secretion in vivo. Moreover, this has largely been achieved without altering their potency at wild-type canine and rat receptors, as judged by their displacement of [125I]-BH-CCK-8S in a radioligand binding assay and by their activity in an isolated, perfused rat stomach bioassay, respectively. 2-(5-Cyclohexyl-1-(2-cyclopentyl-2-oxo-ethyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl)-N-(3-(5-oxo-2,5-dihydro- [1,2,4]oxadiazol-3-yl)-phenyl)-acetamide (47) was identified as the most effective compound stemming from this approach, proving to be a potent inhibitor of pentagastrin-stimulated gastric acid secretion in rats and dogs by intravenous bolus as well as by enteral administration.

3D QSAR studies of 1,3,4-benzotriazepine derivatives as CCK2 receptor antagonists

“…Structurally compound 1 is unique since it is the only one in the training set possessing a N 1 -methyl substituent. According to McDonald et al [32], high receptor affinity will be achieved in the presence of a ketone carbonyl group and a bulky hydrophobic tert-butyl group at the N 1 -position, features that are missing in compound 1. A notable underprediction of pK i values for compounds 32 and 34 stems from the undesirable occupancy of the sterically unfavorable large yellow contour by a 6-substituted indole-and indazole-N 1 -acetic acid functional group, respectively, according to CoMFA steric contour map discussed below.…”

“…The training and the test set used include a series of 1,3,4-benzotriazepine derivatives previously reported as CCK 2 R antagonists [31,32]. The pK i values (Àlog K i ) were used as a dependent variable in the CoMFA, CoMSIA, and HQSAR analyses.…”

“…Other 1,4-benzodiazepine-based CCK 2 antagonists based on the paradigm of compound L-365,260 [23] were compound GR 199114X [26] which lacks a charged functionality, compounds L-736,380 [27] and Z-360 [28] which contain acidic substituents, and compounds L-740,093 [29] and YF476 [30], which contain basic substituents. Consequently, McDonald et al [31] have reported the synthesis of series of 1,3,4-benzotriazepine-based CCK 2 R antagonists which are achiral and maintained selectivity over CCK 1 R. Further, they reported optimization of 1,3,4-benzotriazepine-based CCK 2 R antagonists so as to obtain potent, orally active inhibitors of gastrin-mediated gastric acid secretion [32]. CCK 2 R is a seven-transmembrane spanning receptor that belongs to the superfamily of GPCR's.…”

“…In the present study different 3D QSAR techniques such as comparative molecular field analysis (CoMFA) [38,39] and comparative molecular similarity indices analysis (CoMSIA) [40] were applied to a series of recently discovered achiral 1,3,4-benzotriazepine compounds [31,32] with potent CCK 2 R antagonistic activity so as to correlate molecular property fields of aligned antagonists using the partial least squares (PLS) method [41,42]. Well established rational drug design methods such as CoMFA and CoMSIA have been successfully applied in our laboratory to malonyl CoA decarboxylase inhibitors [43], cytotoxic agents [44] and HCV NS5B polymerase inhibitors [45].…”

Microwave-Assisted Syntheses of Bioactive Seven-Membered, Macro-Sized Heterocycles and Their Fused Derivatives

“…Benzotriazepine derivatives are commonly used for their antibacterial, antiviral, anti-protozoan (plasmodium) and psychotropic activities; series of benzotriazepines have been also designed as potential anti-cancer or anti-viral agents [66][67][68][69] (Figure 11). In addition, some of them have been also used as acaricidal, herbicidal and insecticidal agents.…”