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)

Peptidyldipeptide hydrolase [angiotensin I-converting enzyme, EC 3.4.15.1] was inhibited by inorganic and organic phosphorus compounds tested, except for beta-glycerophosphate, 5'-AMP, and 5'-ADP, at the reagent concentrations used. Orthophosphate and pyrophosphate nonspecifically inhibited the enzyme activity. The enzyme was also inhibited specifically by carboxylates. The degree of inhibition by aliphatic monocarboxylates increased in proportion to their chain length up to C14. Aromatic and omega-phenylalkylcarboxylates also inhibited the enzyme activity. The enzyme was noncompetitively inhibited by acetate, 3-phenylpropionate and laurate. The Ki's for acetate, 3-phenylpropionate, and laurate were 60, 3.3, and 2.5 mM, respectively.
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PMID:Some enzymatic properties of peptidyl dipeptide hydrolase (angiotensin I-converting enzyme). 19 38

The hypotensive efficacy of (S)-1-[6-amino-2[[hydroxy(4-phenylbutyl) phosphinyl]oxy]-1-oxohexyl]-L-proline (SQ 29,852), a phosphorus-containing novel angiotensin converting enzyme inhibitor (ACEI) was examined in conscious two-kidney, one-clip Goldblatt hypertensive dogs. The acute hypotensive effect of SQ 29 852 was compared with that of captopril or enalapril at 3 mg/kg, p.o., for each, and the potencies were ranked as follows, enalapril greater than SQ 29,852 greater than captopril. On the other hand, the hypotension caused by repetitive dosing with SQ 29,852 (3 mg/kg, p.o./d for 7 d followed by another 7-d treatment with 10 mg/kg, p.o./d) was somewhat more marked than that by enalapril at the same dosage. Blood urea nitrogen (BUN) increased in all the animals given enalapril, while that in all of the SQ 29,852-treated animals did not increase. These results indicate that SQ 29,852 is a potent, and long-lasting ACEI with a possible low incidence of side effects.
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PMID:Hypotensive effect of a phosphorus-containing novel angiotensin converting enzyme inhibitor, (S)-1-[6-amino-2[[hydroxy(4-phenylbutyl)phosphinyl] oxy]-1-oxohexyl]-L-proline (SQ 29,852) in conscious hypertensive dogs. 143 66

Relative biological values (BV) of 36 feed phosphates were determined with female turkeys in bioassays of 21-day duration using three response criteria: weight gain, tibia ash percentage, and gain:feed ratio. Calcium phosphate, dibasic dihydrate (United States Pharmacopeia) was the reference standard. Nine mono-dicalcium phosphates (M-DCP, 21.0% phosphorus), 13 di-monocalcium phosphates (D-MCP, 18.5% phosphorus), and 14 defluorinated phosphates (DFP, 18.0% phosphorus) were evaluated. The average relative BV for M-DCP, D-MCP, and DFP samples were 97.6, 94.6, and 90.8%, respectively. Solubility of phosphates was determined by four recognized methods. The solvents were water, .4% HCl, 2.0% citric acid (CA), and neutral ammonium citrate (NAC). Water solubility of M-DCP samples was greater (67.5%) than that of D-MCP (38.8%) and DFP (8.9%) samples. Correlation of water solubility of phosphates to their relative BV was quite low, and water solubility was a poor indicator of BV. When .4% HCl was the solvent, correlation coefficients (r) were .55, .33, and .72 for M-DCP, D-MCP, and DFP, respectively. Based on these results and prediction equations, .4% HCl solubility would be inappropriate for estimating BV of M-DCP and D-MCP samples. Solubility of feed phosphates (mainly D-MCP and DFP) in 2.0% CA or NAC was positively correlated with BV; the r values were .87 to .95. Both of these solubility tests provided a good index of BV. However, it would seem inappropriate and risky to replace bioassays totally with these tests. Feed phosphate users could perform either the 2.0% CA or NAC solubility test easily as a screen for BV along with other quality control procedures (i.e., phosphorus, calcium, sodium, and fluoride determinations).
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PMID:Correlation of biological value of feed phosphates with their solubility in water, dilute hydrogen chloride, dilute citric acid, and neutral ammonium citrate. 147 May 90

The pathogenesis of progressive renal disease includes systemic hypertension and intrarenal factors that may be hemodynamic or metabolic in origin and involve mediators of inflammation. Most current information derives from experiments in rodents. In other species (rabbit, dog, baboon) subjected to renal mass reduction, a greater variety of pathologic changes is apparent than in rats. Clinical trials at controlling progression of renal disease are compounded by numerous factors; and it is not evident that extrapolation can safely be made from results of animal studies to human disease. The mechanism(s) of renal disease progression in humans, therefore, remain largely unknown. Current therapeutic recommendations in patients with chronic renal disease include limitation of phosphorus absorption, correction of lipid abnormalities and control of systemic blood pressure. The latter can be achieved with a variety of agents some of which, like angiotensin converting enzyme inhibitors and calcium antagonists, may be preferred because of specific intrarenal effects.
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PMID:Progression of renal disease: current concepts and therapeutic approaches. 161 70

The effects of (S)-1[6-amino-2[[hydrozy(4- phenylbutyl)phosphinyl]oxy]-1-oxohexyl]-L-proline (SQ 29 852), a phosphorus-containing novel angiotensin converting enzyme inhibitor (ACEI), which is synthesized aiming an ACEI with long-lasting activity and with few side effects, were studied using anesthetized dogs. SQ 29 852 was equipotent with captopril to modify blood pressure response of the animals to angiotensin I (Ang I) and bradykinin (Bdk). An intravenous infusion of SQ 29 852 at 0.1 mg/kg/min for 30 min caused a remarkable hypotension without reflex tachycardia in open-chest dogs. In these animals cardiac contractility (dP/dtmax of left ventricular pressure) appeared to be reduced by SQ 29 852 without any changes in right atrial pressure (RAP), left ventricular end-diastolic pressure (LVEDP) and aortic blood flow (AoF, cardiac output). In sodium-restricted dogs, the hypotension and renal vasodilation by SQ 29 852 (at 0.01, 0.1, and 1 mg/kg, i.v.) were slightly pronounced compared with animals fed with normal diet. It is demonstrated from these results that SQ 29 852 has comparable potency with captopril to inhibit angiotensin converting enzyme (ACE) activity and as common a pharmacological profile as ACEI. SQ 29 852 may be a favorable antihypertensive agent, if its long-lasting activity and few side effects are confirmed.
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PMID:Pharmacology of a phosphorus-containing novel angiotensin converting enzyme inhibitor, SQ 29 852 in anesthetized dogs. 181 74

A clinical trial, to evaluate the effects of a Chinese herbal drug, Rheum E and angiotensin converting enzyme inhibitor, Captopril on chronic renal failure (CRF), was conducted. Thirty cases with initial serum creatinine (Scr) levels of 344.8 +/- 114.0 mumol/L were allocated randomly to 3 groups: Rheum E treated group, Captopril treated group and Rheum E + Captopril group. A control group of 12 cases were on dietary therapy alone. During the 6-22 months of treatment, all the patients were kept on low-protein (0.6g/kg/d), and low-phosphorus (10mg/kg/d) diet. The results showed that the progression rate of renal failure, calculated by regression analysis of 1/Scr vs time, was found to be retarded after treatment with the increased regression coefficient (b value). Scr levels and blood urea nitrogen were kept stable or fell slightly. Albumin rose during the follow-up period (P less than 0.05) in the treated patients, being more marked in both Rheum E and Rheum E + Captopril groups. Uremic symptoms of nausea, anorexia improved in most of the treated patients. It is concluded that long-term low-dose Rheum E taken orally is beneficial to CRF. Its effect is better than that of Captopril. The regime of Rheum E and Captopril is a preferable choice in the long-term treatment for preventing progression of CRF.
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PMID:Clinical effects of rheum and captopril on preventing progression of chronic renal failure. 212 52

Two experiments were conducted to determine the relative biological values (BV) of phosphorus in feed phosphates. Experiment 2 was a replicate of Experiment 1, except that an additional phosphate source was tested. Within experiments, each treatment was replicated twice. Each pen contained eight broiler cockerels. The experimental diets were composed primarily of corn and soybean meal. The reference phosphate [anhydrous, reagent-grade, dibasic calcium phosphate (AR-DCP)] was added to supply five levels of phosphorus. Each phosphate supplement was added to supply two levels of phosphorus. A regression equation was calculated based on logarithm g, nonphytate phosphorus per kilogram of diet versus the percentage of bone ash from chicks fed diets containing AR-DCP. Nonphytate phosphorus equivalents were calculated using the percentage of bone ash from chicks fed the test phosphates. The biological values of the test phosphates were determined as nonphytate phosphorus equivalents, minus the nonphytate phosphorus in the basal diet, divided by the amount of supplemental phosphorus. The BV obtained for the commercial phosphates in Experiments 1 and 2 were: dibasic calcium phosphate, 106 and 104; monobasic calcium phosphate. 102 and 104; defluorinated phosphate (DFP)-1, 88 and 90; and DFP-2, 100.
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PMID:The relative biological value of feed phosphates for chicks. 232 May 22

Five phosphorus-containing inhibitors of angiotensin converting enzyme were found to exhibit slow, tight-binding kinetics by using furanacryloyl-L-phenylalanylglycylglycine as substrate at pH 7.50 and T = 25 degrees C. Two of the inhibitors, (O-ethylphospho)-Ala-Pro (2) and (O-isopropylphospho)-Ala-Pro (3), are found to follow at minimum a two-step mechanism of binding (mechanism B) to the enzyme. This mechanism consists of an initial fast formation of a weaker enzyme-inhibitor complex (Ki = 130 nM for 2 and 180 nM for 3) followed by a slow reversible isomerization to a tighter complex with measurable forward (K3) and reverse (k4) rate constants (k3 = 4.5 X 10(-2) s-1 for 2 and 5.4 X 10(-2) s-1 for 3; k4 = 9.2 X 10(-3) s-1 for 2 and 3.5 X 10(-3) s-1 for 3). For the remaining three inhibitors, phospho-Ala-Pro (1), (O-benzyl-phospho)-Ala-Pro (4), and (P-phenethylphosphono)-Ala-Pro (5), a one-step binding mechanism (mechanism A) is observed under the conditions of the experiment. The second-order rate constants k1 (M-1 s-1) for the binding of these inhibitors to converting enzyme are found to have values more than 3 orders of magnitude lower than the diffusion-controlled limit for a bimolecular reaction involving the enzyme, viz., 3.9 X 10(5) for 1, 2.2 X 10(5) for 4, and 4.8 X 10(5) for 5.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Kinetics of slow, tight-binding inhibitors of angiotensin converting enzyme. 302 47

The synthesis of a series of orally active, phosphinyloxyacyl proline inhibitors of angiotensin converting enzyme (ACE) is described. The in vitro and in vivo ACE inhibitory activities are reported for each compound. The structure-activity relationship for this series of compounds in relation to the carboxyalkyl dipeptide ACE inhibitors as well as other types of hydroxyphosphinyl-containing ACE inhibitors (e.g., the corresponding nitrogen and carbon isosteres) is discussed. Within an isosteric series of phosphorus-containing inhibitors based on the lysylproline terminal dipeptide sequence, only the phosphonates (oxygen isosteres) show a high level of oral activity. Optimum potency and oral activity in the phosphonate series occurs with the (phenylbutyl)- and n-hexylphosphonate side chains. An aminobutyl side chain in the P1' residue is an absolute requirement for full expression of oral activity. The most potent of these compounds, 8b (SQ 29,852), has intravenous and oral activities superior in potency to those of captopril in the normotensive rat.
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PMID:(Phosphinyloxy)acyl amino acid inhibitors of angiotensin converting enzyme (ACE). 1. Discovery of (S)-1-[6-amino-2-[[hydroxy(4-phenylbutyl)phosphinyl]oxy]-1-oxohexyl]-L -proline a novel orally active inhibitor of ACE. 333 20

Recent studies have shown that, not only in hypertensive animals but even in normotensive rats, dietary salt (sodium chloride) produces a dose-related increase in the left ventricular and renal mass. In the present study the effects of the angiotensin converting enzyme inhibitor (ACEI) enalapril and the thiazide-type diuretic, hydrochlorothiazide, on the development of the salt-induced left ventricular and kidney hypertrophy were examined in normotensive Wistar-Kyoto and Wistar rats. A high intake of sodium chloride (6% of the dry weight of the chow to mimic the level found in many human food items) during eight weeks produced a marked increase in the mass of the left ventricle and the kidneys in both rat strains with little or no effect on blood pressure. The cardiac hypertrophy correlated strongly with the renal hypertrophy. These salt-induced changes in the heart and in the kidneys were completely blocked by hydrochlorothiazide, while enalapril was devoid of any significant effects during the high-salt diet. However, during a low-salt diet enalapril, but not hydrochlorothiazide, effectively lowered the blood pressure and decreased the left ventricular mass of the normotensive rats. There was a 3- to 4-fold increase in the urinary excretion of calcium during the high intake of sodium chloride. Hydrochlorothiazide decreased the urinary excretion of calcium even during the low salt diet, and it completely blocked the salt-induced hypercalciuria. Enalapril had no significant effect on the urinary calcium excretion. During the low-salt diet hydrochlorothiazide increased the calcium and decreased the potassium concentration in the heart while enalapril increased the phosphorus concentration. In conclusion, a high intake of sodium chloride produced hypertrophy both in the heart and in the kidneys, even in the absence of a rise in blood pressure. Salt also remarkably increased the urinary calcium excretion. These harmful effects of salt were blocked by the thiazide diuretic hydrochlorothiazide but not by the ACEI enalapril. However, this study does not allow to make any direct comparison between the effects of enalapril and hydrochlorothiazide.
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PMID:Effects of enalapril and hydrochlorothiazide on the salt-induced cardiac and renal hypertrophy in normotensive rats. 784 79


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