Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nineteen planimetric indices of 110 cardiac healthy subjects, 141 patient with left ventricle loading and 136 patients with right ventricle loading are analyzed. On the base of the variation analysis and determination of statistically significant differences, it was established that in right-ventricular loading the following indices deviate from the norm: ASX, AQZ, AQRSX, AQRSz, SAQRSx, SAQRSy, SAQRSz, SAS, SAQRSg, whereas in left-ventricular loading -- ARx, ARz, AQRSx, AQRSz, SAQRx, SAQRSy, SAQRz, SAR, SAQRSg. At a second stage, the sensitivity of the separate indices from the groups with left ventricular and right-ventricular loading was amalyzed, as well as the separate subgroups (pulmonary stenosis, aortic stenosis, mitral stenosis, interauricular defect, arterial hypertension, mitral or aortic insufficiency. The results were compared with those of axial indices, obtained from another investigation of the authors. The planimetric analysis was established to be more complex than the axial and the index SAQRSg to be with the best sensitivity in the cases with hemodynamically lightly loaded musculature.
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PMID:[Planimetric analysis of ventricular depolarization on Frank's corrected orthogonal electrocardiogram in healthy hearts and in patients with ventricular loading]. 52 72

The risks of treating allograft rejection are primarily related to high-dose steroid therapy. To determine when the possible benefit of anti-rejection therapy might not justify the risks, we analysed 20 severe rejection (SAR) episodes for indices of reversibility. Prior renal function was similar in all patients. Ccr fell to 10 ml/min or less, but degree of renal dysfunction was not predictive of reversibility, nor were time since transplant, oliguro/anuria, proteinuria, or hypertension. The only consistent finding was that function began to improve in reversible rejection 3.8 +/- 1 days after beginning therapy. Our rejection treatment, based on this finding, is to use gram doses of IV prednisolone, up to three times in five to seven days. Among 41 patients with 45 grafts so treated, there was no fatality or gastrointestinal haemorrhage. Other complications (fistulae and/or infections) were related to total dose and frequency, to intensive therapy during severe renal dysfunction or to urinary leaks. Limitation of the period of high-dose steroid therapy was associated with reduced morbidity and mortality in renal allograft recipients.
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PMID:Minimising the risks of treating acute allograft rejection. 110 56

Orally-active angiotensin-converting enzyme inhibitors are rapidly establishing themselves in the therapy of hypertension and congestive heart failure. Concerted efforts in a number of laboratories have now led to the discovery or synthesis of an unparalleled variety of potent inhibitors. The manner in which several of these inhibitors bind to ACE is beginning to be understood. It is hoped that some of the insights to be derived from the SAR and structural studies done with ACE inhibitors will be applicable to other enzyme targets as well. The success of ACE inhibitors as pharmacological tools and in the clinic will also quite certainly encourage future efforts to develop new enzyme inhibitor approaches to drug therapy.
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PMID:Recent developments in the design of angiotensin-converting enzyme inhibitors. 299 31

We have identified GR138950, a potent antagonist of the angiotensin II receptor with high oral bioavailability, as our second drug candidate to GR117289. Using GR117289, a compound with moderate bioavailability (20%) in man as a lead, we pursued a strategy aimed at enhancing bioavailability. The strategy was based on SAR established around the diacid GR117289, and from this, it was proposed that a monoacid, in particular a trifluoromethanesulfonamide, should be better absorbed after oral administration and have enhanced oral bioavailability. This led to the identification of GR138950, a potent antihypertensive agent in the renal hypertensive rat, causing sustained falls in blood pressure after oral administration. Oral bioavailability of GR138950 in rats and dogs is high, confirming that GR138950 is well absorbed after oral administration. Moreover, the low plasma clearance and long plasma half-life suggest that this compound will be suitable for once a day administration. Furthermore, the preliminary data indicate that the high bioavailability of GR138950 seen in rats and dogs translates to man. These results demonstrate clearly that GR138950 has the potential to be a clinically effective antihypertensive agent. Further studies are in progress to evaluate GR138950 in the treatment of hypertension.
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PMID:Bromobenzofuran-based non-peptide antagonists of angiotensin II: GR138950, a potent antihypertensive agent with high oral bioavailability. 793 34

The further evolution of the imidazole-5-acrylic acid series of nonpeptide angiotensin II receptor antagonists is detailed (for Part 1, see: J. Med. Chem. 1992, 35, 3858). Modifications of the N-benzyl ring substitution were undertaken in an effort to mimic the Tyr4 residue of angiotensin II. Introduction of a p-carboxylic acid on the N-benzyl ring resulted in the discovery of compounds with nanomolar affinity for the receptor and good oral activity. SAR studies of these potent antagonists revealed that the thienyl ring, the (E)-acrylic acid, and the imidazole ring in addition to the two acid groups were important for high potency. Also, overlay comparisons of the parent diacid with both angiotensin II and a representative biphenylyltetrazole nonpeptide angiotensin II receptor antagonist are presented. The parent diacid analog, SK&F 108566 or (E)-3-[2-butyl-1-(4-carboxybenzyl)-1H-imidazole-5-yl]-2-[(2- thienyl)methyl]propenoic acid, is currently in clinical development for the treatment of hypertension.
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PMID:Potent nonpeptide angiotensin II receptor antagonists. 2. 1-(Carboxybenzyl)imidazole-5-acrylic acids. 851 25

Linear [6.6.6] tricyclic moieties whose center ring is made of two atoms of differing size (here primarily thioxanth-9-ones and phenoxathiins) monosubstituted meta to the sulfur by C(O)NHMe include potent and selective inhibitors of monoamine oxidase A. Similarities with effects on SAR of acylamide and of diazapentacyclic substitution on such rings, including positional variables, the requirement for monomethylation (primary and dialkylated amides are inactive and higher monoalkylated amides show little or no potency), and that sulfur is optimally in sulfone form, suggest that binding to the enzyme occurs similarly in each series. No significantly greater rise in blood pressure was found in rats given sufficient 8 to inhibit most brain and liver MAO A and then followed by oral tyramine than was found on administration of tyramine to controls. This is in contrast to a large blood pressure rise in rats pretreated with phenelzine followed by tyramine, and in accord with the belief that an inhibitor selective for MAO A which is reversibly bound to the enzyme and therefore displaced by any ingested tyramine will not lead to the "cheese effect" (hypertension during treatment with MAO inhibitors usually caused by ingestion of foods containing tyramine).
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PMID:Selective inhibitors of monoamine oxidase. 4. SAR of tricyclic N-methylcarboxamides and congeners binding at the tricyclics' hydrophilic binding site. 925 53

The purpose of this cross-sectional study was to examine the risk associations between obesity indexes [body mass index (BMI) and waist circumference (WC)], cardiovascular risk factors [plasma glucose and lipids, blood pressure and urinary albumin excretion (UAE)] and morbidity conditions (Type 2 diabetes mellitus, hypertension, dyslipidaemia and/or albuminuria) in Hong Kong Chinese. Seven-hundred and two Hong Kong Chinese subjects (18-65 years of age, 59.4% of whom had at least one morbidity condition) were recruited from the Prince of Wales Hospital, Hong Kong SAR. The measurements taken of the subjects included: height; weight; waist and hip circumferences; blood pressure; fasting plasma glucose and lipids; and 24-h UAE. The mean BMI was 22.4 and 25.7 kg m(-2) in healthy subjects and patients, respectively. The mean WC measurements of healthy subjects and patients were 77.1 and 86.4 cm in males and 71.0 and 81.8 cm in females, respectively. There were increasing trends between obesity indexes and the severity of cardiovascular risk factors and the prevalence of morbidity conditions (all P-values for trend <0.05). Using 19.0-20.9 kg m(-2) and <70 cm as a referent, subjects with a BMI of > or =25.0 kg m(-2) (in both sexes) and/or a WC of > or =85 cm in males and > or =75 cm in females had an age-adjusted odds ratio between 3.2 and 4.4 for the occurrence of at least one morbidity condition. Patients with a greater number of comorbidities also had higher BMI and WC measurements (all P-values for the trend were <0.05 with adjustment for age and gender). Hence, despite Hong Kong Chinese being less obese than Caucasians, the intimate relationships among obesity, cardiovascular risk factors and morbidity conditions remain. Our data support using lower BMI and WC levels to define obesity and its associated health risks rather than using the criteria established from Caucasians who generally have larger body frames.
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PMID:Obesity and cardiovascular risk factors in Hong Kong Chinese. 1216 69

The involvement of vasopressin (AVP) in several pathological states has been reported recently and the selective blockade of the different AVP receptors could offer new clinical perspectives. During the past few years, various selective, orally active AVP V1a (OPC-21268, SR49059 (Relcovaptan)), V2 (OPC-31260, OPC-41061 (Tolvaptan), VPA-985 (Lixivaptan), SR121463, VP-343, FR-161282) and mixed V1a/V2 (YM-087 (Conivaptan), JTV-605, CL-385004) receptor antagonists have been intensively studied in various animal models and have reached, Phase IIb clinical trials for some of them. For many years now, our laboratory has focused on the identification of nonpeptide vasopressin antagonists with suitable oral bioavailability. Using random screening on small molecule libraries, followed by rational SAR and modelization, we identified a chemical series of 1-phenylsulfonylindolines which first yielded SR49059, a V1a receptor antagonist prototype. This compound displayed high affinity for animal and human V1a receptors and antagonized various V1a AVP-induced effects in vitro and in vivo (intracellular [Ca2+] increase, platelet aggregation, vascular smooth muscle cell proliferation, hypertension and coronary vasospasm). We and others have used this compound to study the role of AVP in various animal models. Recent findings from clinical trials show a potential interest for SR49059 in the treatment of dysmenorrhea and in Raynaud's disease. Structural modifications and simplifications performed in the SR49059 chemical series yielded highly specific V2 receptor antagonists (N-arylsulfonyl-oxindoles), amongst them SR121463 which possesses powerful oral aquaretic properties in various animal species and in man. SR121463 is well-tolerated and dose-dependently increases urine output and decreases urine osmolality. It induces free water-excretion without affecting electrolyte balance in contrast to classical diuretics (e.g. furosemide and hydrochlorothiazide). Notably, in cirrhotic rats with ascites and impaired renal function, a 10-day oral treatment with SR121463 (0.5 mg/kg) totally corrected hyponatremia and restored normal urine excretion. This compound also displayed interesting new properties in a rabbit model of ocular hypertension, decreasing intraocular pressure after single or repeated instillation. Thus, V2 receptor blockade could be of interest in several water-retaining diseases such as the syndrome of inappropriate antidiuretic hormone secretion (SIADH), liver cirrhosis and congestive heart failure and deserves to be widely explored. Finally, further chemical developments in the oxindole family have led to the first specific and orally active V1b receptor antagonists (with SSR149415 as a representative), an awaited class of drugs with expected therapeutic interest mainly in ACTH-secreting tumors and various emotional diseases such as stress-related disorders, anxiety and depression. However, from the recently described tissue localization for this receptor, we could also speculate on other unexpected uses. In conclusion, the development of AVP receptor antagonists is a field of intensive pharmacological and clinical investigation. Selective and orally active compounds are now available to give new insight into the pathophysiological role of AVP and to provide promising drugs.
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PMID:Nonpeptide vasopressin receptor antagonists: development of selective and orally active V1a, V2 and V1b receptor ligands. 1243 36

The N-methyl-D-aspartate (NMDA) receptor is a ligand-gated ion channel which is widely distributed in the central nervous system (CNS), and which mediates most of the fast excitatory neuronal transmission in the CNS. As with other ligand-gated ion channels, the NMDA receptor is a macromolecular complex which possesses a number of intricate regulatory sites within and around a central ion channel. The key regulatory components for which prototypic antagonists have been developed are the competitive NMDA antagonist binding site, the non-competitive NMDA antagonist binding site within the ion channel, and the NMDA receptor-associated glycine antagonist site. The binding domains for each of these binding sites possess discrete and non-overlapping SAR with regard to the chemical series developed to date. The potential utility of NMDA antagonists in the treatment of stroke and traumatic brain injury was investigated soon after the synthesis of the first bioavailable NMDA antagonists. Efficacy in preclinical models was demonstrated with both competitive and non-competitive NMDA antagonists. However, preclinical testing also revealed potentially clinically-limiting side-effects which included phencyclidine (PCP)-like actions indicative of possible psychotomimetic activity, cerebral vacuolisation of limbic cortical neurones, low therapeutic indices relative to incapacitating motor side-effects and, in the case of non-competitive antagonists, hypertension. These limitations have led to the design of clinical trials that should define the therapeutic index for this type of compound in humans. Currently, the first competitive antagonist to enter clinical trials, selfotel, is on hold, while D-CPPene is still in development. The non-competitive antagonist, aptiganel, is currently in Phase III clinical trials and its therapeutic efficacy and index should be defined in 1997 and 1998. The well-defined limitations of competitive and non-competitive NMDA antagonists have been a key impetus in the investigation of alternative approaches to modulating the NMDA receptor complex. In the case of glycine site antagonists, these compounds have been shown in preclinical studies to be devoid of PCP-like actions and the neuronal vacuolisation associated with the competitive and non-competitive NMDA antagonists. This has induced the development of a number of chemical series with at least three compounds currently in Phase I and II clinical trials. These include ACEA 1021, GV150526A and ZD9379. Clinical efficacies and therapeutic indices of these compounds should be defined in 1998 and 1999. An alternative approach using a partial agonist of the glycine site (1-aminocyclopropane-carboxylic acid, ACPC) has been halted in Phase I. Another approach which has led to the development of NMDA receptor antagonists, selective for the NMDA receptor subunits 1A/2B (NR1A/2B subtype), was the discovery in early studies of the neuroprotective actions of ifenprodil. Structural analogues include eliprodil, CP-101,606 and lubeluzole. In the cases of eliprodil and lubeluzole, these compounds have demonstrated neuroprotection in preclinical models, but they possess the extremely dangerous side-effect of increasing cardiac repolarisation time (i.e., increased QTc interval). The therapeutic index for these compounds is low. This has led to the termination of eliprodil's development and has limited the current dosing strategy with lubeluzole. It has not been disclosed if CP-101,606 possesses this dose-limiting side-effect. In summary, strategies for drug design and development based on our knowledge of the NMDA receptor complex have led to the development of a new generation of compounds for the treatment of stroke and traumatic brain injury, which remain to be evaluated in the clinic. The success of this approach will be defined in the next two to three years.
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PMID:N-methyl-D-aspartate antagonists for stroke and head trauma. 1598 6

The action of renin is the rate-limiting step of the renin-angiotensin system (RAS), a key regulator of blood pressure. Effective renin inhibitors directly block the RAS entirely at source and, thus, may provide a vital weapon for hypertension therapy. Our efforts toward identifying novel small-molecule peptidomimetic renin inhibitors have resulted in the design of transition-state isosteres such as 1 bearing an all-carbon 8-phenyl-octanecarboxamide framework. Optimization of the extended P3 portion of 1 and extensive P2' modifications provided analogues with improved in vitro potencies in the presence of plasma. X-ray resolution of rh-renin/38a in the course of SAR work surprisingly unveiled the exploitation of a previously unexplored pocket (S3sp) important for strong binding affinities. Several inhibitors demonstrated oral efficacy in sodium-depleted marmosets. The most potent, 38a, induced dose-dependently a pronounced reduction in mean arterial blood pressure, paralleled by complete blockade of active plasma renin, up to 8 h post-dose. Oral bioavailability of 38a was 16% in marmosets.
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PMID:Novel 2,7-dialkyl-substituted 5(S)-amino-4(S)-hydroxy-8-phenyl-octanecarboxamide transition state peptidomimetics are potent and orally active inhibitors of human renin. 1782 79


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