New nonpeptide angiotensin II receptor antagonists. 1. Synthesis, biological properties and structure-activity relationships of 2-alkylbenzimidazole derivatives

Thomas, Andrew P.; Allott, Christopher P.; Gibson, K. H.; Major, John S.; Masek, Brian B.; Oldham, Alec A.; Ratcliffe, Arnold H.; Roberts, David A.; Russell, Simon T.; Thomason, D. A.

doi:10.1021/jm00083a011

Cited by 102 publications

(39 citation statements)

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“…The AT 1 blocker ZD 7155 was generously supplied by Zeneca (Planckstadt, Germany). ZD 7155 is a recently synthesized compound (Thomas et al, 1992) that speci®cally blocks AT 1 but not AT 2 receptors Abdelrahman et al, 1993) and appears to be more potent and longer acting than the prototype AT 1 blocker losartan (Junggren et al, 1996). The AT 2 blocker PD 123319 (Timmermans et al, 1993) was a generous gift by Dr Th.…”

Section: Drugsmentioning

confidence: 99%

Endogenous angiotensin II and the reflex response to stimulation of cardiopulmonary serotonin 5HT₃ receptors

Veelken

Hilgers

Scrogin

et al. 1998

British J Pharmacology

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1 Angiotensin (Ang) II modulates cardiovascular barore¯exes; whether or not the peptide in¯uences chemosensitive cardiovascular re¯exes is not known. We tested the hypothesis that Ang II modulates the re¯ex control of sympathetic nerve activity exerted by 5-hydroxytryptamine 3 (5HT 3 ) cardiopulmonary receptors. 2 The 5HT 3 receptor agonist phenylbiguanide (PBG), infused intravenously for 15 min, elicited a sustained re¯ex decrease of renal sympathetic nerve activity (RSNA) but only transient (53 min) changes of arterial blood pressure (BP) and heart rate (HR) in methohexital-anaesthesized rats. 3 Infusion of Ang II at a dose that did not aect baseline BP, HR and RSNA enhanced the PBGevoked re¯ex decrease of RSNA (754+5% in Ang II treated versus 733+6% in control rats after 15 min PBG, P50.05, n=6 each) in methohexital-anaesthetized rats. 4 The angiotensin converting enzyme (ACE) inhibitor lisinopril blunted the re¯ex responses to PBG in anaesthetized as well as conscious animals. The eect of the ACE inhibitor was abolished by concomitant infusion of Ang II. 5 The re¯ex response to stimulation of cardiopulmonary 5HT 3 aerents was also impaired by the Ang II type 1 receptor (AT 1 ) blocker ZD7155 but not by the type 2 (AT 2 ) blocker PD 123319. 6 Infusion of a volume load to stimulate cardiopulmonary baroreceptors induced a gradual decrease of RSNA which was impaired by exogenous Ang II (RSNA 726+6% in Ang II treated versus 747+6% in control rats after volume load, P50.05, n=6 each) but unaected by ACE inhibition. 7 The re¯ex control of RSNA by cardiopulmonary 5HT 3 receptors is enhanced by Ang II via AT 1 receptors. Thus, Ang II facilitates a chemosensitive cardiovascular re¯ex, in contrast to its inhibitory in¯uences on mechanosensitive re¯exes.

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Section: Drugsmentioning

confidence: 99%

Endogenous angiotensin II and the reflex response to stimulation of cardiopulmonary serotonin 5HT₃ receptors

Veelken

Hilgers

Scrogin

et al. 1998

British J Pharmacology

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“…Alkylation of benzimidazole and benzotriazole with 3 (BPE, R 1 = Br) to prepare, respectively, the ester 12 and 13 analogues has already been reported [16]. Here, we now present the results of the reaction of both 5-methylbenzimidazole 14a and 2,5-dimethylbenzimidazole 14b with methyl 4'-(bromomethyl)biphenyl-2-carboxylate 3, first to prepare the esters 15 and then hydrolyse these into the acids 16.…”

Section: Resultsmentioning

confidence: 85%

Alkylation of azoles: Synthesis of new heterocyclic‐based AT₁‐non‐peptide angiotensin (II) receptor antagonists

Al‐Azmi

George

El‐Dusouqui

2007

Journal of Heterocyclic Chem

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Several novel analogues of Losartan 2 were synthesized as potential non-peptide angiotensin (II) receptor antagonists. In these non-peptide analogues, the tetrazole and the substituted imidazole rings of Losartan 2 were replaced, respectively, by a carboxylic acid function or its methyl ester and substituted triazole, imidazole or benzimidazole moieties. The biphenyl bromide precursor 3 (BPE) used to introduce the linker between the acid/ester function and the heterocyclic moiety was synthesized using Suzuki biphenyl coupling and then incorporated into the target molecule by simple nucleophilic substitution. The fixed N-aryl isomeric forms of several azole and benzimidazole tautomers were successfully separated by HPLC using 50% aqueous acetonitrile as eluent. Intermediate reaction products and final target compounds were fully characterized spectroscopically.

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“…By D-optimal design, 18 out of the original 28 compounds were selected. The 10 leftover molecules are compounds 2, 12, 15,17,18,21,22,24,25 and 28, which could be used as an external set, although we fully agree that this would be a biased set and anyway not a real test set.…”

Section: Molecule Selectionmentioning

confidence: 79%

A 3D QSAR CoMFA study of non-peptide angiotensin II receptor antagonists

Belvisi

Bravi

Catalano

et al. 1996

J Computer-Aided Mol Des

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A series of non-peptide angiotensin II receptor antagonists was investigated with the aim of developing a 3D QSAR model using comparative molecular field analysis descriptors and approaches. The main goals of the study were dictated by an interest in methodologies and an understanding of the binding requirements to the AT1 receptor. Consistency with the previously derived activity models was always checked to contemporarily test the validity of the various hypotheses. The specific conformations chosen for the study, the procedures invoked to superimpose all structures, the conditions employed to generate steric and electrostatic field values and the various PCA/PLS runs are discussed in detail. The effect of experimental design techniques to select objects (molecules) and variables (descriptors) with respect to the predictive power of the QSAR models derived was especially analysed.

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New nonpeptide angiotensin II receptor antagonists. 1. Synthesis, biological properties and structure-activity relationships of 2-alkylbenzimidazole derivatives

Cited by 102 publications

References 1 publication

Endogenous angiotensin II and the reflex response to stimulation of cardiopulmonary serotonin 5HT₃ receptors

Endogenous angiotensin II and the reflex response to stimulation of cardiopulmonary serotonin 5HT₃ receptors

Alkylation of azoles: Synthesis of new heterocyclic‐based AT₁‐non‐peptide angiotensin (II) receptor antagonists

A 3D QSAR CoMFA study of non-peptide angiotensin II receptor antagonists

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New nonpeptide angiotensin II receptor antagonists. 1. Synthesis, biological properties and structure-activity relationships of 2-alkylbenzimidazole derivatives

Cited by 102 publications

References 1 publication

Endogenous angiotensin II and the reflex response to stimulation of cardiopulmonary serotonin 5HT3 receptors

Endogenous angiotensin II and the reflex response to stimulation of cardiopulmonary serotonin 5HT3 receptors

Alkylation of azoles: Synthesis of new heterocyclic‐based AT1‐non‐peptide angiotensin (II) receptor antagonists

A 3D QSAR CoMFA study of non-peptide angiotensin II receptor antagonists

Contact Info

Product

Resources

About

Endogenous angiotensin II and the reflex response to stimulation of cardiopulmonary serotonin 5HT₃ receptors

Endogenous angiotensin II and the reflex response to stimulation of cardiopulmonary serotonin 5HT₃ receptors

Alkylation of azoles: Synthesis of new heterocyclic‐based AT₁‐non‐peptide angiotensin (II) receptor antagonists