Controlled Modification of Acidity in Cholecystokinin B Receptor Antagonists:  N-(1,4-Benzodiazepin-3-yl)-N ‘-[3-(tetrazol-5-ylamino)phenyl]ureas

Abstract

The design, synthesis, and biological activity of a novel series of CCK-B receptor antagonists (1) which incorporate a tetrazol-5-ylamino functionality attached to the phenyl ring of the arylurea moiety of L-365,260 are described. In these compounds, the acidity of the tetrazole was gradually modified by utilization of simple conformational constraints, and X-ray crystallographic data were obtained to support the conformational depenence of the pK(a) of the aminotetrazoles. Compounds to emerge from the present work such as 1f and 2c,d are among the highest affinity and, in the case of 1f, most selective (CCK-A/CCK-B, 37 000) antagonists so far reported for this receptor. The C(5)-cyclohexyl compound 2c (L-736,380) dose-dependently inhibited gastric acid secretion in anesthetized rats (ID(50), 0.064 mg/kg) and ex vivo binding of [(125)I]CCK-8S in BKTO mice brain membranes (ED(50), 1.7 mg/kg) and is one of the most potent acidic CCK-B receptor antagonists yet described.

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

“…Initial efforts aimed at creating chiral 1,4-and 1,5-benzodiazepine-based CCK 2 antagonists led to the development of compound (L-365,260) [23], a 1,4-benzodiazepine, whose biological testing has progressed to human studies that showed its capability of reversing the anxiogenic effects produced by tetragastrin [24], but its ineffectiveness in patients with panic disorder [25]. 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].…”

Synthesis, radiolabeling and evaluation of novel amine guanidine derivatives as potential positron emission tomography tracers for the ion channel of the N-methyl-d-aspartate receptor

“…The N-(3-aminophenyl)-N-methylcyanamide intermediates 17e19 were prepared from 3-nitro-aniline 8. Cyanamide 15 was obtained in 93% yield [32]. After methylation of the cyanamide moiety and reduction of the nitro moiety, 17 was obtained in 72% overall yield.…”

Cholecystokinin antagonists: Pharmacological and therapeutic potential

“…Therefore, further modifications were performed on the tetrazole moiety of L-368,730 in order to influence bioavailability by modulating the pK A of the acidic moiety by means of structural manipulations around the tetrazole group. 157 From this study, the aminotetrazole group was chosen as acidic moiety, because its pK A (6.0) is substantially higher than that of the tetrazole itself. Compounds resulting from this strategy, such as L-736,380 (27) and its analogue L-738,425, in which a 2-tetrazolyl-isoindolyl moiety replaces the 3-(N-methyl-N-tetrazolyl)aminophenyl of 27, are among the most potent and, in the case of L-738,425 [CCK 2 IC 50 ¼ 0.11 nM, CCK 1 /CCK 2 ¼ 37,000], most selective CCK 2 antagonists so far reported.…”

“…However, these acidic compounds are significantly less brain penetrant than the prototype L-365,260 (22). 157 Only with the introduction of cationic water solubilizing groups, particularly within the C-5 substituent, the oral bioavailability was improved. Such strategy was initially prompted by the 4-fold increase in plasma concentration after oral dosing in rats, with respect to L-365,260, achieved in the case of the 2-pyridyl substituted derivative 28.…”