Nonpeptide angiotensin II receptor antagonists. 1. Synthesis and in vitro structure-activity relationships of 4-[[[(1H-pyrrol-1-ylacetyl)amino]phenyl]methyl]imidazole derivatives as angiotensin II receptor antagonists

A novel series of non-biphenylyltetrazole angiotensin II receptor antagonists which contain a 1H-pyrrol-1-ylacetyl residue in place of the benzoyl residue in EXP 6803 have been developed. The receptor binding activity of several members of this new series was in the 10(-8) M range, which was better than that of EXP 6803. Introduction of a carboxylic acid moiety at the 2-position of the pyrrole ring enhanced the in vitro binding affinity at the receptor by 10-fold. Compounds containing an acetic acid (18) or a propionic acid residue (20) at the 5-position of the imidazole were more potent than the carboxylic acid analogue (24). The binding IC50 of the most potent compound 20 was 22 nM. Compounds 18, 20, and 24 in their best fit conformations were manually overlayed on that of the template conformation of EXP 6803 and EXP 8623, respectively. The synthesis and structure-activity relationship data are described.     

Nonpeptide angiotensin II receptor antagonists. Synthesis and biological activity of potential prodrugs of benzimidazole-7-carboxylic acids

In order to improve the oral bioavailability (BA) of 2-butyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimid azole - 7-carboxylic acid (3: CV-11194) and 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4- yl]methyl]-1H-benzimidazole-7-carboxylic acid (4: CV-11974), novel angiotensin II (AII) receptor antagonists, chemical modification to yield prodrugs has been examined. After selective tritylation of the tetrazole rings in 3 and 4, treatment of N-tritylated benzimidazole-7-carboxylic acids (6, 7) with a variety of alkyl halides, followed by deprotection with hydrochloric acid, afforded esters of 3 and 4. Mainly 1-(acyloxy)alkyl esters and 1-[(alkoxycarbonyl)oxy]alkyl esters, double ester derivatives, were synthesized. Their inhibitory effect on AII-induced pressor response in rats and oral BA were investigated. (Pivaloyloxy)methyl and (+/-)-1-[[(cyclohexyloxy)-carbonyl]oxy]ethyl esters of 3 and 4 showed marked increases in oral bioavailability which significantly potentiated the inhibitory effect of the parent compounds on AII-induced pressor response. Among them, (+/-)-1-[[(cyclohexyloxy)carbonyl]oxy]ethyl 2- ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimida zole- 7-carboxylate (10s, TCV-116) was selected as a candidate for clinical evaluation.     

Active metabolites derived from angiotensin II

Stasis of viscid secretions in cystic fibrosis (CF) leads to chronic infection, inflammation, and lung destruction. Chest physiotherapy (CPT) has been used for many years to assist in the removal of these secretions. However, the need for independently administered CPT exists, particularly for adolescents and the older CF patient. Two devices, the intrapulmonary percussive ventilator (IPV) and the Flutter device (Flutter) have been promoted for this purpose. This study compares these devices to standard, manual CPT. There was no difference in sputum quantity produced with any method studied. Transiently lower oxygen saturation was noted with standard CPT compared with the IPV and Flutter. Inconsistent but significant improvements in flow rates were noted with the two devices compared to standard CPT. Important trends to lower lung volumes, probably indicating decreased air trapping, were also noted with all three therapies at 1 and 4 hours after administration. There were no adverse effects with any treatment regimen. Larger and longer studies of these devices compared to standard CPT and with each other are warranted to assess their value for independent administration of CPT in CF patients and to determine long-term effects on maintenance of pulmonary function.     

Studies on nonpeptide angiotensin II receptor antagonists. III. Synthesis and biological evaluation of 5-alkylidene-3,5-dihydro-4H-imidazol-4-one derivatives

The ITS-2 sequences from seven worms of the Japanese triploid form of Fasciola, two of Fasciola hepatica from Uruguay and four of Fasciola gigantica from Zambia and Indonesia were determined. The ITS-2 sequences of the Japanese triploid worms were divided into two distinct types, one of which was almost identical to that of F. hepatica and the other to F. gigantica from Indonesia.     

4-Diazinyl- and 4-pyridinylimidazoles: potent angiotensin II antagonists. A study of their activity and computational characterization

A series of N-[biphenylyl(tetrazolyl)methyl]-2-butylimidazoles containing variously substituted diazine or pyridine moieties either as their free bases or N-oxide derivatives attached to the 4-position of the imidazole ring was synthesized and tested for interaction with the AT1 receptors of rat adrenal cortex membranes (receptor binding assay). Some compounds were then chosen for further evaluation in vivo in the A II-induced pressor response in conscious normotensive rats. The most potent in the AT1 binding assay were found to be compounds in which the diazine or pyridine ring nitrogen is adjacent to the point of attachment between the two heteroaromatic rings such as 2-butyl-4-(3,6-dimethylpyrazin-2-yl)-1-[[2'-(1H-tetrazol-5-y l)-biphenyl-4- yl]methyl]-1H-imidazole (3b) or 2-butyl-4-[5-(methoxycarbonyl)pyrid-2-yl]-1-[[2'-(1H-tetrazol++ +-5- yl)biphenyl-4-yl]methyl]-1H-imidazole (6c). The binding affinities and oral activities of the pyridine N-oxide imidazoles in which a stabilizing group ortho to the pyridine ring nitrogen is present were markedly improved as in 2-butyl-4-[(3-methoxycarbonyl)-6-methyl-N-oxopyridin-2-yl]-1-[[2'- (1H- tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-imidazole 31b. Molecular modeling studies were carried out to determine the molecular electrostatic potential values of related model systems and to correlate their receptor interaction energies with the observed activities of our compounds.     

Hemodynamic effects of angiotensin II and the influence of angiotensin receptor antagonists in pithed rabbits

We investigated the cardiovascular effects of angiotensin II (AII) and the influences of four angiotensin receptor antagonists: losartan, PD123177, BIBS 39, and BIBS 222 in the pithed rabbit preparation. AII (0.03-10 nmol/kg) elicited a dose-dependent increase in blood pressure (BP), left ventricular pressure (LVP), LV end-diastolic pressure (LVEDP), dP/dtmax, and heart rate (HR). The maximal hypertensive effect of AII is comparable to that of norepinephrine (NE), but its effects on LVEDP and HR are weaker than those of NE. On a molar base, AII is approximately 27 times more potent than NE. Propranolol (0.5 mg/kg i.v.) did not significantly influence the AII-induced increase in diastolic BP (DBP) and LVEDP, but it abolished AII-induced positive chronotropic effects over the entire dose range of angiotensin AII studied. Losartan, but not PD123177, shifted the dose-response curves for AII to the right in a parallel manner. BIBS 39 and BIBS 222 also caused rightward shifts of the AII dose-response curve. These experiments indicate that in propranolol-treated pithed rabbits AII causes vasoconstrictor effects in both resistance vessels and in the venous system, which are both mediated by AT1- but not by AT2-receptors. The AII-induced positive chronotropic effect is an indirect action mediated by the stimulation of postsynaptic beta 1-adrenoceptors. BIBS 39 and BIBS 222, two new nonpeptide angiotensin receptor blockers that have affinity for both AT1- and AT2-receptors are also potent antagonists of the cardiovascular effects of AII in pithed rabbits.     

Antihypertensive therapy. Angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, and calcium antagonists

ACEIs, angiotensin II receptor antagonists, and calcium antagonists are effective and well-tolerated antihypertensive agents but, except in special situations, should be considered alternative drugs for first line therapy until randomized trials show that they are at least as effective as diuretics and beta-blockers in preventing cardiovascular morbidity and mortality for a broad spectrum of hypertensive patients. ACEIs are particularly indicated for managing patients with congestive heart failure due to systolic dysfunction and patients with diabetic nephropathy, especially in Type I diabetes. Theoretically, the AII receptor antagonists will be equally effective for these indications, and randomized trials are now underway to demonstrate this. Special indications for calcium antagonists in the management of hypertension include angina pectoris, and for the non-dihydropyridine calcium antagonists, paroxysmal supraventricular tachycardia, and atrial fibrillation with rapid ventricular rate. Isolated systolic hypertension in the elderly is a special indication for long-acting dihydropyridine calcium antagonists, although diuretics are preferred. Calcium antagonists have been particularly effective in managing hypertension induced by cyclosporine. They are contraindicated in CHF due to systolic dysfunction and in the management of acute myocardial infarction. The long-term cardioprotective effect of calcium antagonists after a myocardial infarction has been demonstrated only for verapamil and diltiazem in patients with no evidence of LV dysfunction during their infarction. Calcium antagonists should be prescribed for this purpose only when beta-blockers are poorly-tolerated or contraindicated.     

A new series of imidazolones: highly specific and potent nonpeptide AT1 angiotensin II receptor antagonists

Starting from the structure of the novel nonpeptide AT1 receptor antagonist DuP 753 (losartan), a new series of potent antagonists was designed. In these compounds the central imidazole nucleus was replaced by the dihydroimidazol-4-one structure. The most active compounds had a spirocyclopentane or a spirocyclohexane ring in position 5. Like the imidazole series, the best substituents were the linear butyl chain in position 1 and the [2'-(tetrazol-5-yl)biphenylyl]methyl group in position 3. Antagonistic activity was assessed by the ability of the compounds to competitively inhibit [125I]AII binding to the AT1 subtype receptor and to antagonize AII-induced contractions in rabbit aorta rings. The most active compounds had IC50 values in the nanomolar range. In conscious rats, compounds 4 and 21 antagonized the AII pressor response when administered orally. Compound 21 (SR 47436) was the most active; it was recently shown to also be active in cynomolgus monkeys both intravenously and orally. This molecule is now undergoing clinical trials for the treatment of hypertension.     

Production of [Asn1, Val5] angiotensin II and [Asp1, Val5] angiotensin II in kallikrein-treated trout plasma (T60K)

Incubation of heat-denatured plasma from the rainbow trout Oncorhynchus mykiss with porcine pancreatic kallikrein generates, in addition to bradykinin-related peptides, previously uncharacterized peptides that contract mammalian and amphibian vascular smooth muscle. Using rings of vascular smooth muscle from the bullfrog systemic arch as bioassay, we have isolated two myotropic peptides whose primary structures were established as: Asn-Arg-Val-Tyr-Val-His-Pro-Phe ([Asn1, Val5]angiotensin II) and Asp-Arg-Val-Tyr-Val-His-Pro-Phe ([Asp1, Val5]angiotensin II). These peptides are the same as those generated in salmon plasma by an extract of kidney. The data raise the possibility that activation of the kallikrein-kinin system in trout generates both bradykinin-related and angiotensin II-related peptides that may act synergistically in the regulation of blood pressure.     

Design and synthesis of nonpeptide angiotensin II receptor antagonists featuring acyclic imidazole-mimicking structural units

Extensive molecular modelling studies, including conformational analysis and the comparison of molecular electrostatic potential distributions, wee used to evaluate structural parameters of new antagonists containing acyclic replacements of the N = C-N imidazole region. The synthesis and the biological screening of a series of acyl biphenyltetrazole derivatives were planned and realized to gain an insight into the structure-activity relationships of this unusual class of Angiotensin II antagonists.     

Structural evolution and pharmacology of a novel series of triacid angiotensin II receptor antagonists

cis-4-(4-Phenoxy)-1-[1-oxo-2(R)-[4-[(2-sulfobenzoyl)amino)-1H- imidazol-1-yl]octyl]-L-proline derivatives represent a novel class of potent nonpeptide angiotensin II (Ang II) receptor antagonists. These compounds evolved from directed structure-activity relationship (SAR) studies on a lead identified by random screening. Further SAR studies revealed that acidic modification of the 4-phenoxy ring system produced a series of triacid derivatives possessing oral activity in pithed rats. The most potent compound, cis-4-[4-(phosphonomethyl)phenoxy]-1-[1-oxo-2(R)-[4-[(2-sulfobenzoyl+ ++) amino]-1H-imidazol-1-yl]octyl]-L-proline (1e), inhibited the pressor response to exogenously administered Ang II for periods up to 8 h following oral dosing. The antihypertensive activity of 1e was evaluated in the Lasix-pretreated conscious spontaneously hypertensive rat (SHR) where it produced a dose-dependent fall in blood pressure following oral dosing lasting > 12 h. Antagonists such as 1e may serve as useful therapeutic agents for the treatment of hypertension as well as for studying the role of Ang II in various disease states.     

Synthesis and pharmacological evaluation of 1-methyl-5-[substituted-4 (3H)-oxo-1,2,3-benzotriazin-3-yl]-1H-pyrazole-4-acetic acid derivatives

Several new 1-methyl-5-[substituted-4-oxo-1,2,3-benzotriazin-3-yl] -1H-pyrazole-4-acetic acids and their ethyl ester derivatives were prepared. The compounds were tested for analgesic and antiinflammatory activities, acute toxicity, ulcerogenic effect, and as in vitro inhibitors of 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD), since it is claimed that the inhibition of such an enzyme predicts in vivo antiinflammatory activity. Some compounds were more active than phenylbutazone in the phenylbenzoquinone and acetic acid peritonitis tests, and equiactive to the same drug in the carrageenin paw edema test. All the compounds inhibited the 3 alpha-HSD, but no correlation was observed with the paw edema inhibition values. The compounds proved to possess marginal or no ulcerogenic effect, as well as low systemic toxicity.     

Angiotensin-converting enzyme inhibitors but not angiotensin II AT 1 receptor antagonists affect erythropoiesis in patients with anemia of end-stage renal disease

PURPOSE: To report the successful treatment of choroidal detachment in a patient with nanophthalmos and to report histopathologic findings in this patient's sclera. METHODS: Choroidal detachment, secondary angle closure, and nanophthalmos were diagnosed using biomicroscopy, indirect ophthalmoscopy, and echography. Full-thickness sclerectomies in four quadrants were made on the right eye. Sclerae from these sclerectomies were studied ultrastructurally. RESULTS: Best-corrected visual acuity improved to RE, 20/60 from 20/100 preoperatively; the anterior chamber deepened, and the choroidal detachment resolved. Histopathologic studies of each of the three scleral layers disclosed abnormal collagen fibrils that were frayed, split, and contained lightly stained cores. CONCLUSION: New findings include the identification of collagen with lightly stained centers and identification of differences in collagen morphology in different areas of the sclera in a nanophthalmic eye.     

1,8-disubstituted analogues of (Ile5) and (Val5)angiotensin II: difference in potency and specificity of angiotensin II-antagonistic activity

Depending on the species, position 5 in angiotensin II is occupied by isoleucine or valine. 1,8-disubstituted analogues of [Ile5]angiotensin II show distinct differences from the corresponding [Val5]angiotensin II analogues in the potency and specificity of their inhibitory action. The syntheses of new analogues are described.     

3-Acetyl-4-aryl-5-oxo-2,7,7-trimethyl-1,4,5,6,7,8-hexahydro-quinoline derivatives and their calcium antagonistic activities

Thirteen 3-acetyl-4-aryl-5-oxo-2,7,7-trimethyl-1,4,5,6,7,8- hexahydroquinoline derivatives (5a-m), one of which was synthesized before, have been prepared. The structures of the products 5b-m were characterized by IR,1H-NMR and elemental analysis. The calcium antagonistic activity of these compounds was studied in rabbit taenia coli precontracted with 1 mmol/l Ca+2.     

Growth response of human coronary smooth muscle cells to angiotensin II and influence of angiotensin AT1 receptor blockade

BACKGROUND: Adolescents and young adults are four times more likely to be victims of sexual assault than women in all other age groups. In the vast majority of these cases, the perpetrator is an acquaintance of the victim. Date rape is a subset of acquaintance rape where nonconsensual sex occurs between two people who are in a romantic relationship. METHODS: We conducted a MEDLINE and Current Concepts search for articles relating to date rape and then systematically reviewed all relevant articles. RESULTS: Lifetime prevalence of date or acquaintance rape ranges from 13% to 27% among college-age women and 20% to a high of 68% among adolescents. Demographic characteristics that increase vulnerability to date rape include younger age at first date, early sexual activity, earlier age of menarche, a past history of sexual abuse or prior sexual victimization, and being more accepting of rape myths and violence toward women. Other risk factors include date-specific behaviors such as who initiated, who paid expenses, who drove, date location and activity, as well as the use of alcohol or illicit drugs such as flunitrazepam (Rohypnol). Alcohol use that occurs within the context of the date can lead to: the misinterpretation of friendly cues as sexual invitations, diminished coping responses, and the female's inability to ward off a potential attack. CONCLUSIONS: Longitudinal research designs are needed to further our understanding of sexual violence among adolescents and young adults and the most effective ways to eliminate it. Understanding and comparing research findings would be easier if consensus regarding the definitions of date rape, sexual aggression, and sexual assault was obtained. Finally, primary and secondary date and acquaintance rape prevention programs must be developed and systematically evaluated.