Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.15.1 (ACE)
18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Four primary zinc-binding pharmacophores (thiols, carboxylates, phosphorus acids, and hydroxamates) have been utilized in generating inhibitors of zinc metalloproteases such as ACE, NEP, the MMPs, and ECE. Although compounds which inhibit the activity of both ACE and NEP (vasopeptidase inhibitors, VPIs) have been reported which incorporate a thiol, carboxylate, or phosphorus acid pharmacophore, the generation of hydroxamate based vasopeptidase inhibitors has remained elusive. Herein we report the first potent vasopeptidase inhibitors which were generated from the incorporation of conformationally restricted dipeptide mimetics to an N-formyl hydroxylamine zinc-binding group. Compounds such as 13c and 13d are among the most potent in this series, exhibiting in vitro activity comparable to other classes of inhibitors.
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PMID:N-formyl hydroxylamine containing dipeptides: generation of a new class of vasopeptidase inhibitors. 1069 48

The effect of angiotensin converting enzyme (ACE) inhibitor, temocaprilat and/or angiotensin II type 1 (AT1) receptor antagonist, CV-11974 on myocardial metabolism and contraction during ischemia and reperfusion was examined by phosphorus 31-nuclear magnetic resonance (31P-NMR) in Langendorff rabbit hearts. After normothermic 15 min global ischemia, postischemic reperfusion of 60min was carried out. Temocaprilat and/or CV-11974 were administered from 40 min prior to the global ischemia. Adenosine triphosphate (ATP), creatine phosphate (PCr), inorganic phosphate (Pi), intracellular pH (pHi), left ventricular developed pressure (LVDevP), left ventricular end-diastolic pressure (LVEDP) and coronary flow were measured. Twenty-eight hearts were divided into 4 experimental groups consisting of 7 hearts each: group I consisted of controls, group II was perfused with temocaprilat (10(-6)mol/L), group III was perfused with CV-11974 (10(-6)mol/L), and group IV was perfused with temocaprilat (10(-6)mol/L) in combination with CV-11974 (10(-6) mol/L). Groups II and III showed a significant (p<0.05) inhibition of an overshoot phenomenon of PCr during postischemic reperfusion compared with group I. Group IV also showed a more pronounced significant (p<0.01) inhibition of the overshoot of PCr during reperfusion compared with group I. Groups II, III and IV showed a significant (p<0.05) inhibition of the decrease in ATP during global ischemia (59+/-2, 54+/-3 and 54+/-7%, respectively) compared with group I (45+/-3%). Groups II and IV showed a significant (p<0.05) early recovery of ATP during reperfusion (81+/-2, 80+/-6%) compared with group I (71+/-3%) and group II (73+/-2%). Group IV showed no more significant recovery in ATP than group III. There were no differences in LVDevP, LVEDP and coronary flow among these groups. In conclusion, temocaprilat in combination with CV-11974 has significant potential for improving myocardial energy metabolism during both myocardial ischemia and reperfusion.
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PMID:Effect of angiotensin converting enzyme inhibitor and angiotensin II type 1 receptor antagonist on metabolism and contraction in ischemia-reperfused rabbit heart. 1078 50

The submillimeter-wave rotational spectra of the unstable phosphorus-bearing molecules HCCCP (phosphabutadiyne) and NCCP (C-cyanophosphaethyne) have been investigated in selected frequency regions between 490 and 815 GHz using the Cologne Terahertz Spectrometer. Both molecules were studied in their ground vibrational states. Additionally, vibrational satellites within the bending states v(4) = 1 and v(5) = 1 were recorded for NCCP. Furthermore, the ground state rotational spectra of the (13)C and (15)N isotopomers of NCCP were detected in natural abundance. The new measurements allowed us to evaluate the sextic centrifugal distortion constants for each isotopomer and vibrational state investigated. The pyrolysis reactions, through which HCCCP and NCCP were produced in situ, also yielded phosphaethyne, HCP, as a by-product. Some transitions of HCP and DCP were recorded in their ground vibrational states along with v(2) = 1 vibrational satellites of the former. Copyright 2001 Academic Press.
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PMID:Submillimeter-Wave Spectroscopy of Phosphaalkynes: HCCCP, NCCP, HCP, and DCP. 1114 14

Although angiotensin converting enzyme (ACE) inhibitor and/or angiotensin II type 1 (AT1) receptor antagonist can protect the myocardium against ischemia-reperfusion injury, the mechanisms of the effect have not yet been characterized at the cellular level. We here examined the effect of the combination of an ACE inhibitor, temocaprilat, an AT1 receptor antagonist, CV-11974 and/or a nitric oxide synthase inhibitor, L-NAME, on the myocardial metabolism and contraction during ischemia and reperfusion by using phosphorus 31-nuclear magnetic resonance (31P-NMR) in Langendorff rabbit hearts. After normothermic 20 min global ischemia, postischemic reperfusion of 30 min was carried out. Twenty-one hearts were divided into three experimental groups consisting of 7 hearts each: a Tem+CV group perfused with a combination of temocaprilat and CV-11974; a Tem+CV+L-NAME group perfused with a combination of temocaprilat and CV-11974 plus L-NAME, and a control group. During ischemia, both the Tem+CV group and Tem+CV+L-NAME group showed a significant inhibition of the decrease in adenosine triphosphate (ATP) compared with the control group (p<0.01); the increase in ATP was 50+/-3%, 42+/-4%, and 19+/-4% in the Tem+CV group, Tem+CV+L-NAME group, and control group, respectively. Both experimental groups also showed a significant inhibition of the increase in left ventricular end-diastolic pressure (LVEDP) compared with the control group (p<0.01). After postischemic reperfusion, the Tem+CV group and Tem+CV+L-NAME group again showed a significant improvement of ATP as compared with the control group (p<0.01); the increase in ATP was 73+/-3%, 64+/-3%, and 47+/-4% in the Tem+CV group, Tem+CV+L-NAME group, and control group, respectively, and a significant decrease of LVEDP as compared with the control group (p<0.01). There were no differences in ATP, or LVEDP during ischemia and reperfusion between the Tem+CV group and Tem+CV+ L-NAME group. In conclusion, the combination of temocaprilat and CV-11974 showed significant potential for improving myocardial energy metabolism and relaxation during both myocardial ischemia and reperfusion. This beneficial effect was not dependent on NO synthase.
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PMID:Cardioprotection with angiotensin converting enzyme inhibitor and angiotensin II type 1 receptor antagonist is not abolished by nitric oxide synthase inhibitor in ischemia-reperfused rabbit hearts. 1151 Jul 53

We investigated the effects of a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, pravastatin, an angiotensin converting enzyme (ACE) inhibitor, temocaprilat, and an angiotensin II type 1 (AT1) receptor antagonist, CV-11974, on myocardial metabolism during ischemia in isolated rabbit hearts using phosphorus 31-nuclear magnetic resonance (31P-NMR) imaging. Forty-five minutes of continuous normothermic global ischemia was carried out. Pravastatin, temocaprilat, CV-11974 or a nitric oxide synthase inhibitor, L-NAME was administered from 60 min prior to the global ischemia. Japanese white rabbits were divided into the following experimental groups, a control group (n=7), a group treated with pravastatin (P group; n=7), a group treated with pravastatin and temocaprilat (P+T group; n=7), a group treated with pravastatin and CV-11974 (P+CV group; n=7), and a group treated with pravastatin and L-NAME (P+L-NAME group; n=7). During ischemia, P group, as well as either P+T group or P+CV group, showed a significant inhibition of the decreases in adenosine triphosphate (ATP) and intracellular pH (pHi) (p<0.01, respectively, at the end of ischemia compared to the control group as well as P+L-NAME group), and a significant inhibition of the increase in inorganic phosphate (Pi) (p<0.01, respectively, compared with the control group as well as P+L-NAME group). These results suggest that pravastatin significantly improved myocardial energy metabolism during myocardial ischemia. This beneficial effect was dependent on NO synthase. However, this beneficial effect was not enhanced by either temocaprilat or CV-11974.
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PMID:Effects of an HMG-CoA reductase inhibitor in combination with an ACE inhibitor or angiotensin II type 1 receptor antagonist on myocardial metabolism in ischemic rabbit hearts. 1204 36

Water treatment residuals (WTRs) are a by-product of municipal drinking water treatment plants and can have the capacity to adsorb tremendous amounts of P. Understanding the WTR phosphorus adsorption process is important for discerning the mechanism and tenacity of P retention. We studied P adsorbing mechanism(s) of an aluminum-based [Al2(SO4)3 x 14H2O] WTR from Englewood, CO. In a laboratory study, we shook mixtures of P-loaded WTR for 1 to 211 d followed by solution pH analysis, and solution Ca, Al, and P analysis via inductively coupled plasma atomic emission spectroscopy. After shaking periods, we also examined the solids fraction by X-ray diffraction (XRD) and electron microprobe analysis using wavelength dispersive spectroscopy (EMPA-WDS). The shaking results indicated an increase in pH from 7.2 to 8.2, an increase in desorbed Ca and Al concentrations, and a decrease in desorbed P concentration. The pH and desorbed Ca concentration increases suggested that CaCO3 controlled Ca solubility. Increased desorbed Al concentration may have been due to Al(OH)4 formation. Decreased P content, in conjunction with the pH increase, was consistent with calcium phosphate formation or precipitation. The system appeared to be undersaturated with respect to dicalcium phosphate (DCP; CaHPO4) and supersaturated with respect to octacalcium phosphate [OCP; Ca4H(PO4)3 x 2.5H2O]. The Ca and Al increases, as well as OCP formation, were supported by MINTEQA2 modeling. The XRD and EMPA-WDS results for all shaking times, however, suggested surface P chemisorption as an amorphous Al-P mineral phase.
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PMID:Phosphorus retention mechanisms of a water treatment residual. 1453 30

Due to the impressive cardiovascular (CV) morbidity and mortality in uremic patients, assessment of CV risk factors in the dialysis population is a crucial challenge in nephrology. Cardiovascular risk factors in dialysis patients may have a different significance in ESRD patients compared to the general population. The Framingham risk equation seems not to be valid in chronic uremia. Furthermore, new powerful outcome predictors have emerged in recent years: pulse pressure, dipping status, pulse wave velocity, augmentation index. The concept of "U"-shaped association between blood pressure (as well as cholesterolemia) and mortality are extensively discussed. The authors are focusing on the value of office and ambulatory blood pressure measurements in the uremic population. An extensive evaluation of blood pressure and vascular compliance in dialysis patients is proposed. Efficient dialysis, ACE-inhibitors and beta-blockers, statins, antiplatelet treatment and adequate control of calcium-phosphorus metabolism should be the mainstay of therapy in the ESRD patients with several CV risk factors.
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PMID:The challenge of cardiovascular risk factors in end-stage renal disease. 1469 49

Hemodialysis as a therapeutic procedure in patients being in the end-stage of renal failure has been used since the sixties of the 20th century. Generally speaking, the conservative drug therapy in patients treated by hemodialysis is complex, and economically it consummes as great proportion of financial expenses. The aim of the study was to perform an economic analysis of 101 patients, both sexes (37 females and 64 males, aged from 22 to 81 years) treated by hemodialysis, in respect of drug treatment costs. The total average cost of treatment medication represented 161,589 SKK/patient/year. Eighty one percent of total expenses were linked with the consumption on antianemic drugs (102,298.40 SKK/patient/year). The second most expensive drug group (9% of the total cost) were medications used in coincidence with hemodialysis complications (14,981 SKK/patient/year). Diuretic--furosemid was the most frequently used drug out of the category of antihypertensive medications (68% of patients), followed by beta-blockers (preparation Concor), calcium channel blockers (preparations Norvasc and Plendil) and angiotensin converting enzyme tritace inhibitors (ACEI, preparations Trirace, Enap, Prestarium), respectively. Only 27% of patients were treated by hypolipidemic drugs mostly by the preparations of Gevilon and Innogen. In the majority of patients (93%) preparations for the correction of calcium and phosphorus metabolisms such as Vitacalcin and Rocaltrol were administered, the latter being most expensive. Antianemic drugs have been used in all patients. In this category of preparations, those composing acid folate and erythropoetin were used most frequently. Alkaline supplementation of NaHCO, (bicarbonate) was used in 88% of patients. In order to prevent the development of thrombosis and other vascular complications, the drugs with antiaggregative effects were used (Ibustrin, Curantyl, Anopyrin). To prevent the manifestation of gastrointestinal adverse reactions, the administration of H2-antagonists have been preferred (Famosan, Quamtel). The group of "Other drugs" was represented by vitamins and drugs with anti-uratic effects (ascorbic acid--preparation Celaskon, tocopherol--preparation E-vitamin and Milurit). When summed together, the costs of therapy in patients treated by hemodialysis are three times higher compared with those in the pre-dialysis phase. In addition to the latter hemodialysis is associated with a large number of medical, psychic and social complications. In the presented pilot study the authors analysed the financial expenses coinciding with drug costs (direct loads) which are significant, but represent only a part of the pharmacoeconomic complexity. In the future it is necessary to perform a more complex pharmacoeconomic analysis in order to evaluate also other factors, such as the costs of hospitalization, dialysate solutions, technologys, salaries of the staff, etc. (Tab. 6, Ref. 37.).
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PMID:Pharmacoeconomic aspects of patients treated by hemodialysis. 1505 34

In two fattening trials (in each 100 broilers kept in four groups with 25 animals) as well as in a balance trial (four groups with four broilers in a group) the effects of inorganic phosphorus sources [monocalcium phosphate (MCP), dicalcium phosphate (dihydrate; DCP) and defluorinated phosphate (DFP)] in broiler diets were examined. The four diets contained up to 9 g calcium and 6 g phosphorus per kg and comparable energy and nutrient contents. Controls were fed a commercial diet with Ca-Na-phosphate as inorganic phosphorus source supplemented by phytase. In both fattening trials body weight gain, feed consumption and feed conversion were proved as well as the calcium and phosphorus levels in serum, the breaking strength of tibia or humerus and the femur mineralization (ash content in the fat free dry matter). Furthermore, in the balance trial the retention of calcium and phosphorus was determined by calculation (intake minus excretion) as well as by analysis of body composition. On a high performance level (that was only slightly influenced by the different treatments), the addition of DFP resulted in significantly reduced phosphorus availability (estimated by analysis of the whole carcass: control/MCP/DCP/DFP: 48.6/46.0/45.7/35.5%). The significantly reduced phosphorus level in serum (1.77 +/- 0.20/1.77 +/- 0.24/1.73 +/- 0.28 1.34 +/- 0.33 mmol/l) indicates the lower phosphorus retention in broilers given DFP. Furthermore, the crude ash content (582 +/- 17.6/580 +/- 18.6/563 +/- 15.2/547 +/- 29.7 g/kg fat free DM) and the breaking strength of bones (in right tibia in trial 2: 232 +/- 82.4/227 +/- 51.5/232 +/- 41.7/196 +/- 655 N) were lowest when given DFP. For diagnostic purposes it is of special interest that the phosphorus levels in the serum reflected markedly the different concentrations of available phosphorus in the diet.
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PMID:Effects of different phosphorus sources in the diet on bone composition and stability (breaking strength) in broilers. 1578 83

Dialkylsilanediols have been found to be an effective functional group for the design of active-site-directed protease inhibitors, including aspartic (HIV protease) and metallo (ACE and thermolysin) proteases. The use of silanediols is predicated on its resemblance to the hydrated carbonyl transition-state structure of amide hydrolysis. This concept has been tested by replacing the presumed tetrahedral carbon of a thermolysin substrate with a silanediol group, resulting in an inhibitor with an inhibition constant K(i) = 40 nM. The structure of the silanediol bound to the active site of thermolysin was found to have a conformation very similar to that of a corresponding phosphonamidate inhibitor (K(i) = 10 nM). In both cases, a single oxygen is within bonding distance to the active-site zinc ion, mimicking the presumed tetrahedral transition state. There are binding differences that appear to be related to the presence or absence of protons on the oxygens attached to the silicon or phosphorus. This is the first crystal structure of an organosilane bound to the active site of a protease.
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PMID:Structural analysis of silanediols as transition-state-analogue inhibitors of the benchmark metalloprotease thermolysin. 1634 43


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