Novel, Achiral 1,3,4-Benzotriazepine Analogues of 1,4-Benzodiazepine-Based CCK₂ Antagonists That Display High Selectivity over CCK₁ Receptors

Abstract

A series of 1,3,4-benzotriazepine-based CCK(2) antagonists have been devised by consideration of the structural features that govern CCK receptor affinity and the receptor subtype selectivity of 1,4-benzodiazepine-based CCK(2) antagonists. In contrast to the latter compounds, these novel 1,3,4-benzotriazepines are achiral, yet they display similar affinity for CCK(2) receptors to the earlier molecules and are highly selective over CCK(1) receptors.

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

“…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.…”

“…The least energy conformation was determined and subsequently subjected to minimization with the same criteria as mentioned above, and used as a template to build structures of all other training and test set compounds. The conformation of compound 30 was compared with structurally related truncated (7-bromo-5-phenyl-1,3,4-benzotriazepin-2-one) analog for which X-ray crystal data (CCDC Code: QEQXEP) is available [31]. The superimposition of all heavy atoms of the 1,3,4-benzotriazepine core of compound 30 to the corresponding heavy atoms of the truncated analog resulted in rmsd of 0.646, thus the conformation of compound 30 obtained from simulated annealing was a reasonable choice as a template molecule.…”

“…The highly active compounds 16 (pK i = 9.19), 17 (pK i = 8.97), 25 (pK i = 9.18), and 26 (pK i = 9.44), possessing a -COOH group linked through a variety of linkers to the anilide ring, were found to be in contact with the large white contour. McDonald et al [31] have pointed out that the anilide binding site might be exposed to the solvent, as a result, be able to tolerate substituents with varying bulkiness as well as electronic properties. The presence of a white (hydrophobic unfavorable or alternatively hydrophilic favorable) contour map at R 2 -position, further reinforces the suggestion of McDonald et al [31] that this site is probably solvent-exposed.…”

“…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].…”