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)

The angiotensin I-converting enzyme (peptidyl-dipeptide hydrolase, EC 3.4.15.1) inhibitor, ramiprilat (2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-Ala]-(1S,3S,5S)-2- azabicyclo[3.3.0]octane-3-carboxylic acid), is shown to exist in tow conformational isomers, cis and trans, which interconvert around the amide bond. The two conformers were separated by reversed-phase high-performance liquid chromatography. The conformers were identified by nuclear Overhauser effect measurements. From line shape analysis the isomerization rate constants were determined to be kcis----trans = 15 s-1 and ktrans----cis = 5 s-1 at 368 K in [2H]phosphate buffer (p2H 7.5). By enzyme kinetic studies using 3-(2-furylacryloyl)-L-Phe-Gly-Gly as substrate, the trans conformer was found to be the most potent enzyme inhibitor, whereas the cis conformer had a very low inhibitory effect. A new inhibition mechanism is presented for this type of slow, tight-binding inhibitors that contain an amide bond. This mechanism involves an equilibrium between the two conformers and the enzyme-bound inhibitor complex.
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PMID:Cis-trans isomerization of an angiotensin I-converting enzyme inhibitor. An enzyme kinetic and nuclear magnetic resonance study. 217 61

The heptapeptide Met5-enkephalin-Arg6-Phe7 (YGGFMRF) is cleaved at a high rate by tissue peptidases including dipeptidyl carboxypeptidase. The inhibitor, Hoe 498 diacid (2-[N-[(S)-1-carboxy-3-phenylpropyl]-L-alanyl]-(1S,3S,5S)-2-azabicyclo- [3.3.0] octane-3-carboxylic acid), was found to be highly effective in blocking YGGFMRF degradation by a dipeptidyl carboxypeptidase present in a preparation of mouse striatal microsomes. The recovery of YGGFMRF released from rat striatal slices was increased in the presence of Hoe 498 diacid. Furthermore, the recovery of YGGFMRF injected into the caudate was increased in rats pretreated i.p. with Hoe 498 diacid. After i.v. or i.p. injections both Hoe 498 diacid and its prodrug Hoe 498 monoester (2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S,5S)-2- azabicyclo [3.3.0] octane-3-carboxylic acid) were detected in rat cerebrospinal fluid and the dipeptidyl carboxypeptidase activity in cerebrospinal fluid was inhibited. These observations indicate that endogenously released YGGFMRF is protected from degradation by Hoe 498 diacid and that systemically administered Hoe 498 diacid or monoester penetrate the blood-brain barrier and inhibit brain and cerebrospinal fluid dipeptidyl carboxypeptidase activity. This potent inhibitor may be useful to block YGGFMRF inactivation in studies of the pharmacology and physiology of YGGFMRF. It is also possible that some of the cerebral effects of these compounds may be referable to an enhancement of YGGFMRF action in the central nervous system.
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PMID:Inhibition of Met5-enkephalin-Arg6-Phe7 degradation by inhibitors of dipeptidyl carboxypeptidase. 294 3

The effect of the angiotensin converting enzyme inhibitor 2-[N-[(S)-1-carboxy-3-phenylpropyl]-L-alanyl]-(1S,3S,5S)-2- -azabicyclo(3.3.0)octane-3-carboxylic acid (Hoe 498 diacid) and the aminopeptidase inhibitor bestatin on antinociception induced in rats by intraventricular injections of [Met5]enkephalin-Arg6-Phe7 and [Met5]enkephalin-Arg6-Gly7-Leu8 was investigated. Potentiation and prolongation of the antinociception was observed after pretreatment with bestatin. Further potentiation of the antinociception elicited by the heptapeptide was obtained in rats pretreated with a combination of bestatin and Hoe 498 diacid. In contrast, antinociception elicited by the octapeptide was not potentiated further by pretreatment with the bestatin and Hoe 498 diacid combination.
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PMID:Effect of peptidase inhibitors on [Met5]enkephalin-Arg6-Phe7 and [Met5]enkephalin-Arg6-Gly7-Leu8-induced antinociception. 294 92

General pharmacological properties of (+)-(1S,3S,5S)-2-[(S)-N-[(S)-1-ethoxycarbonyl-3-phenyl-propyl] alanyl]-2-azabicyclo[3.3.0]octane-3-carboxylic acid (ramipril, Hoe 498), a new prodrug non-sulfhydryl angiotensin converting enzyme inhibitor and its active diacid metabolite, ramiprilat, were examined. Both ramipril and ramiprilat were without effect on basal central and autonomic nervous systems in rats and mice. Ramipril given intravenously to anaesthetized normotensive dogs produced a slight fall in blood pressure but did not significantly alter other cardio-hemodynamic functions. Also, ramiprilat was without effect on isolated atria and airway resistance of guinea pigs. Oral administration of ramipril to dogs increased renal blood flow but did not significantly affect other renal parameters, for example, glomerular filtration rate and electrolyte excretion. Ramipril produced a competitive inhibition of late proximal tubular secretion which points to in part renal secretory excretion of ramipril and/or its metabolites. Compared to urea-induced diuresis in rats, ramipril was without direct diuretic activity. Ramipril exerted little, if any, influence on gastric bile and pancreatic secretion or intestinal transit in rats, as well as on concentration of glucose and lipoproteins, blood coagulation, platelet aggregation and vascular permeability in rats, rabbits or dogs. The carrageenin-induced rat paw edema was enlarged by ramipril, but there was no such effect on serotonin-, dextran- or ovalbumin-induced edemas which in contrast to carrageenin do not involve bradykinin. Thus, undesired cutaneous reactions might result from locally released bradykinin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:General pharmacology of ramipril. 297 47

Paw oedema in the rat by carrageenin and kaolin partially caused by Hageman factor activation was potentiated by the new angiotensin converting enzyme (ACE) inhibitor 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl-L-alanyl]-(lS,3S,5S)-2- azabicyclo[3.3.0]octane-3-carboxylic acid] (ramipril, Hoe 498) due to its inhibition of kininase II which results in increased bradykinin levels. A dose of 1 microgram ramipril injected into the hind paw of Sprague-Dawley rats concomitantly with, or 1 mg/kg given orally 30 min before administration of the irritants, led to significantly increased inflammatory reactions. The same effects were observed when ramipril was administered 3 h after carrageenin. In the kallikrein-kinin-deficient Brown-Norway rat strain Mai Pfd/f, ramipril did not significantly alter the paw oedema induced as described above. In addition, pretreatment of Sprague-Dawley rats with 10 mg/kg i.v. bromelains completely prevented the potentiation of inflammation by ramipril. Paw oedema provoked by the Hageman factor non-activators serotonin, dextran, ovalbumin and anti-rat IgG was not potentiated by ramipril. The chronic adjuvant arthritis in Lewis rats was not influenced by daily oral treatment with 0.1-3 mg/kg ramipril. Thus, in the rat only those inflammatory reactions involving kinins, presumably generated by Hageman factor activators, are potentiated by ramipril and presumably by other ACE-inhibitors.
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PMID:Influence of the new angiotensin converting enzyme inhibitor ramipril on several models of acute inflammation and the adjuvant arthritis in the rat. 302 36

The humoral and antihypertensive activities of the angiotensin converting enzyme (ACE) inhibitor 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S, 3S, 5S)-2-azabicyclo[3.3.0] octane-3-carboxylic acid (ramipril, Hoe 498) were investigated in 10 patients with essential hypertension (WHO stage I or II). After a 7-day placebo period, the patients were treated with 5 mg ramipril orally once daily for 14 days. Peak serum concentrations of the active metabolite M1 (dicarboxylic acid) of 5.4-62.0 ng/ml were observed 2-6 h after the first oral dose. The maximum ACE inhibition of 95% was reached 2-4 h after the first oral dose, inhibition exceeded 70% 24 h after dosing. The maximum drop in the systolic and diastolic blood pressure (random zero sphygmomanometer) was measured 4 h after ramipril (p less than 0.02, p less than 0.01), but blood pressure on days 7 and 14 of the treatment period was not different from pretreatment values. Automatically recorded blood pressure results showed a marked reduction of both systolic and diastolic blood pressure during treatment compared to placebo. No side effects occurred. From the present data it is concluded that ramipril is a potent ACE inhibitor in hypertensive patients and that further controlled studies are required for the evaluation of the antihypertensive effect of 5 mg ramipril in essential hypertension.
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PMID:Humoral and blood pressure effects of the angiotensin converting enzyme inhibitor ramipril in essential hypertension. 302 38

The convergent, diastereoselective synthesis of 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S,5S)-2- azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe acid (Hoe 498), a new ACE-inhibitor with improved bioavailability and pharmacokinetics, is described.
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PMID:Synthesis of a highly active angiotensin converting enzyme inhibitor: 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S,5S)-2- azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498). 609 64

The interaction of angiotensin converting enzyme (ACE) with 2-[N-[(S)-1-carboxy-3-phenylpropyl]-L-alanyl]-(1S,3S,5S) - 2 - azabicyclo[3.3.0]octane - 3 - carboxylic acid (Hoe 498 diacid) and its ester 2-[N-[(S)-1-ethoxycarbonyl-3 - phenylpropyl] - L - alanyl]-(1S,3S,5S)- 2-azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498) was studied at pH 7.5 in the presence of 300 mmol/l sodium chloride with furanacryloyl-Phe-Gly-Gly as substrate. Hoe 498 diacid inhibits ACE with a Ki value of 7 pmol/l. It is both a slow-and tight-binding inhibitor; the mode of inhibition is fully competitive. Binding of Hoe 498 diacid to ACE proceeds by a two-step mechanism E+I in equilibrium EI in equilibrium EI* in which the inhibitor rapidly binds to enzyme to form an initial enzyme-inhibitor complex which then undergoes a slow isomerization. The interaction of Hoe 498 diacid with ACE is compared to that of the two other potent inhibitors, captopril and enalaprilat.
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PMID:Inhibition of angiotensin converting enzyme by 2-[N-[(S)-1-carboxy-3-phenylpropyl]-L-alanyl]-(1S,3S,5S)-2-azabicyclo [3.3.0]octane-3-carboxylic acid (Hoe 498 diacid). Comparison with captopril and enalaprilat. 609 66

2-[N-[(S)-1-Ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S,5S) - 2-azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498) can be characterized as a novel orally active non-sulfhydryl containing angiotensin converting enzyme inhibitor. Designed as a prodrug to improve the bioavailability Hoe 498 has to be deesterified to its active moiety Hoe 498-diacid to develop full inhibitory potency. The present study compares the basic pharmacological properties of Hoe 498 in rats and dogs to those of enalapril. In vitro assays revealed equal potency of both Hoe 498-diacid and enalaprilat. In vivo the inhibitory potency was judged by the ability to attenuate the pressor response induced by angiotensin I. The results indicate that Hoe 498 was approximately 10 times more potent than enalapril after oral intake in conscious rats or after intraduodenal administration in anaesthetized rats, whereas after intravenous injection both compounds exhibited equal potency. Hoe 498 was at least twice as potent as enalapril after oral or intraduodenal administration in dogs but about 4 times more potent than enalapril after intravenous injection. In conclusion, the obtained data point to a prodrug pathway for Hoe 498 which should be advantageous with regard to bioavailability, onset and duration of action and therefore promises to be favourable in the treatment of different cardiovascular diseases.
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PMID:Pharmacological properties of the new orally active angiotensin converting enzyme inhibitor 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl] -(1S,3S,5S)-2-azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498). 609 67

A highly sensitive and specific enzymatic assay for the quantitative determination of 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S, 5S)-2-azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498) and its hydrolysis product Hoe 498-diacid in serum and a GLC method for the simultaneous determination of both compounds in urine are described. Both methods involve extraction from the respective biological fluid using disposable C 18 columns. In serum, the enzyme-inhibiting properties of Hoe 498-diacid (Hoe 498 can readily be converted to its hydrolysis product) are utilized for the determination of both compounds concurrently. The serum extract is dissolved in buffer solution and incubated with human serum as angiotensin converting enzyme (peptidyl-dipeptide-hydrolase, EC 3.4.15.1) source and hip-his-leu substrate. The hippuric acid liberated is quantitated by HPLC. The urine extract is treated with diazomethane followed by trifluoroacetic anhydride to convert Hoe 498 and Hoe 498-diacid to their methylester, trifluoroacetyl derivatives, which are then determined simultaneously by GLC using a nitrogen specific detector.
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PMID:Determination of 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S,5S)-2- azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498) and its hydrolysis product in serum and urine. 609 70


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