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)

A novel renin inhibitor, YM-21095 [2RS), (3S)-3-[N alpha-[1,4-dioxo-4-morpholino-2-(1-naphthylmethyl)-buthyl]-L- histidil-amino]-4-cyclohexyl-1-[(1-methyl-5-tetrazolyl)thio]-2-but anol), has been synthesized in our laboratories. The aim of this study was to evaluate the pharmacological properties of YM-21095 in in vitro and in vivo experiments. YM-21095 inhibited human renin with an IC50 value of 4.7 x 10(-10) mol/L. YM-21095 was also a potent inhibitor against squirrel monkey renin, but less effective against renins from dog, rabbit, and rat. The effect of YM-21095 is highly specific for renin, since it did not inhibit cathepsin D, pepsin, or angiotensin converting enzyme up to a concentration of 10(-4) mol/L. YM-21095 was resistant to proteolytic actions of the enzymes (pepsin, chymotrypsin, trypsin) and squirrel monkey tissue homogenates (liver, kidney, small intestine). Intravenous infusion of YM-21095 (0.1 to 100 micrograms/kg/min) decreased mean blood pressure and inhibited plasma renin activity in a dose-dependent manner with no effect on heart rate in anesthetized sodium-depleted and sodium-replete squirrel monkeys. The hypotensive effect of YM-21095 in sodium-depleted squirrel monkeys was about ten times as potent as that in sodium-replete squirrel monkeys. Oral administration of YM-21095 to conscious sodium-depleted squirrel monkeys produced dose-related decreases of systolic blood pressure. We conclude that YM-21095 is a potent and highly specific inhibitor of primate renin and produces a blood pressure lowering effect.
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PMID:Pharmacological properties of YM-21095, a potent and highly specific renin inhibitor. 181 49

A newly synthesized orally active renin inhibitor, N-morpholinoacetyl-(1-naphthyl)-L-alanyl-(4-thiazolyl)-L-alanyl (3S,4S)-4-amino-3-hydroxy-5-cyclohexylpentanoyl-n-hexylamide (ES-8891), was found to be a highly potent competitive inhibitor of human renin with an inhibition constant of 1.1 nM. This inhibitor was also active against monkey renin, although there was less inhibition of renin in pig, rabbit, and rat. ES-8891 did not inhibit cathepsin D, pepsin, trypsin, chymotrypsin, angiotensin converting enzyme, and urinary kallikrein at a concentration of 10(-5) M. A single oral administration of ES-8891 (10 or 30 mg/kg) to conscious, sodium-depleted marmosets caused a dose-related decrease in plasma renin activity and blood pressure. ES-8891 (30 mg/kg) produced an 80% inhibition of plasma renin activity, which lasted for more than 6 hours. Kidney renin messenger RNA was not significantly changed 6 hours after oral administration of ES-8891 (30 mg/kg). A single oral administration of 240 mg ES-8891 to healthy human volunteers (n = 6) produced a significant inhibition of plasma renin activity (75% inhibition at 0.5 and 1 hour, 50% inhibition at 2 hours) with a good correlation of plasma levels of ES-8891. There were no significant changes in blood pressure or heart rate, and no adverse effects were observed. These results suggest that ES-8891 is an orally active human renin inhibitor that may be clinically useful.
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PMID:ES-8891, an orally active inhibitor of human renin. 211 12

1. An in vitro experiment was carried out to compare the inhibitory effect of SQ29,852 on human renal angiotensin converting enzyme (ACE) with those of captopril, enalapril and enalaprilat. 2. SQ29,852 strongly inhibited human renal ACE; its IC50 value was 1.5 x 10(-8) M. In terms of the IC50, SQ29,852's efficacy was about 1/10 of that of captopril and 1/28 of that of enalaprilat, but it was about 14 times more potent than enalapril. 3. SQ29,852 showed no inhibitory effects on cathepsin D, urinary kallikrein, renal renin, pepsin, trypsin and chymotrypsin. Its ACE-specificity was higher than that of captopril. 4. ACE inhibition by SQ29,852 was shown to be competitive, as revealed by Lineweaver-Burk plots. The affinity of SQ29,852 to ACE was shown to be high by a Ki value of 1.2 x 10(-8) M.
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PMID:Effect of SQ29,852, a new angiotensin converting enzyme (ACE) inhibitor with a phosphonic acid group, on the activity of angiotensin converting enzyme from human kidney. 216 61

A compound containing cyclostatine ES-6864 (N-[(2R)-3-morpholinocarbonyl-2-(1-naphthylmethyl)propionyl]-(4-th iazolyl)- L-alanyl-cyclostatine-(2-morpholinoethyl)amide) was found to be a competitive inhibitor of human renin with an inhibitory constant (Ki) value of 7.3 x 10(-9) M. The compound was also potent against monkey renin but was less effective against renins from pig, goat, dog, rabbit and rat. ES-6864 did not inhibit cathepsin D, pepsin, urinary kallikrein, angiotensin converting enzyme, trypsin and chymotrypsin at a concentration of 10(-5) M. ES-6864 also inhibited the tissue renin-like activity from dog tissues with IC50 values of 10(-7)-10(-8) M in vitro. Oral administration of ES-6864 at 30 mg/kg to conscious, sodium-depleted marmosets produced a significant blood pressure reduction and a significant inhibition of plasma renin activity, which persisted for 6 hours. Plasma concentration of ES-6864 reached a maximum of 1.2 micrograms/ml at 1 hour after an oral administration. Oral administration of ES-6864 to hog renin-infused rats produced dose-related decreases in blood pressure. The results demonstrate that ES-6864 is an orally active renin inhibitor with high potency and specificity for human renin. Thus, ES-6864 is a candidate compound for development of renin inhibitors that can be used clinically.
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PMID:[In vitro and in vivo inhibition of renin by a thiazolylalanyl cyclostatine derivative]. 251 1

N-alpha-[(S)-1-carboxy-3-phenylpropyl]-L-lysyl-L-proline (MK-0521) is a new non-sulfhydryl-containing angiotensin converting enzyme (ACE) inhibitor. The present investigation describes its ACE and other enzymes inhibitory properties and compares it to those of captopril, MK-421 and MK-422 in vitro. MK-0521 inhibited rat pulmonary ACE by 50% (IC50) at a concentration of 3 nM and was 6.13 times more potent than captopril. The IC50 values of MK-421 and MK-422 against ACE were 2,000 nM and 3.5 nM, respectively. MK-0521 had practically no inhibitory activities against carboxypeptidase A, carboxypeptidase B, leucine aminopeptidase, papain, pepsin and trypsin. The kinetic study on the inhibitory activity of M-0521 against ACE using Lineweaver-Burk plots indicated that MK-0521 exerted competitive ACE inhibition. The dialysis study conducted on the ACE-MK-0521 complex revealed that the inhibitory effect of MK-0521 against ACE was reversible. In the guinea pig ileum, MK-0521 potentiated the contractile effect of bradykinin and depressed the contractile effect of angiotensin I. These effects on bradykinin and angiotensin I were 33.11 and 2.63 times more potent than that of captopril, respectively. The present results suggest that MK-0521 may show a potent hypotensive effect in vivo.
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PMID:[Inhibitory effect of N-alpha-[(S)-1-carboxy-3-phenylpropyl]-L-lysyl-L-proline (MK-0521) on angiotensin converting enzyme in vitro]. 254 78

1. Angiotensin II (AII) acts as a potent pressor agent directly, by virtue of its vasoconstrictor activity and indirectly, by the volume expansion resulting from stimulation of aldosterone release from the adrenal cortex, leading to sodium and water retention. Various approaches of interfering with the enzymatic cascade leading to the production of AII have been made in an attempt to define therapeutic agents for the control of hypertension and heart failure. 2. AII receptor antagonists, to date, lack oral activity and have a relatively short duration of action, limiting their clinical usefulness. Inhibitors of angiotensin converting enzyme block AII production, are orally active and have been used successfully in the control of hypertension and in the treatment of congestive heart failure. 3. An ideal approach to the blockade of the renin-angiotensin system (RAS) is the inhibition of renin, an enzyme with only one known substrate (angiotensinogen) which catalyzes the first and rate-limiting step in the RAS. Early attempts to discover a renin inhibitor focused on immunologic inhibitors of renin, fragments of the prorenin sequence and compounds related to pepstatin, a potent pentapeptide inhibitor of pepsin and less potent inhibitor of renin. None of these approaches proved feasible for a variety of reasons including poor absorption, short duration of action and weak activity. 4. Substrate analogs offer the greatest promise for clinically useful renin inhibitors. Most recently, synthesis of compounds mimicking the enzyme transition state, the condition of greatest binding affinity, has resulted in renin inhibitors with potencies in the nanomolar range, which have shown hypotensive activity. These compounds contain at least one peptide bond and have limited oral activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Renin inhibitors: specific modulators of the renin-angiotensin system. 265 8

Two ketomethylene-containing nonapeptide analogues were synthesized to determine if ketomethylene analogues of the nonapeptide venom inhibitors of angiotensin converting enzyme (ACE) would have oral ACE inhibition activity. Both ketomethylene-containing nonapeptides 18 and 19 were potent inhibitors of rabbit lung ACE with I50s of 3.4 and 8.0 nM, respectively, compared to 340 nM for their parent nonapeptide and 450 nM for captopril. Peptide 18 was rapidly cleaved by trypsin, but 19 was reasonably stable to all enzyme degradation systems tested with maximum degradation of 50% by pepsin in 3 h. Both 18 and 19 when given iv to normotensive rats were between 3 and 10 times more potent than captopril in inhibiting an angiotensin I induced blood pressure increase. Peptide 19 showed no ACE inhibition activity in unanesthetized normotensive rats when administered orally at doses of 10 or 100 mg/kg. Experiments were conducted to determine whether 19 is adsorbed from the gastrointestinal track following oral administration. These experiments indicated that 19 is adsorbed. It is concluded that the lack of oral activity of 19 is probably due to its rapid excretion, probably into the bile.
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PMID:Synthesis and biological activity of ketomethylene-containing nonapeptide analogues of snake venom angiotensin converting enzyme inhibitors. 283 64

The use of fluoro ketones as inhibitors of hydrolytic enzymes has been investigated. The acetylcholine analogues 6,6-dimethyl-1,1,1-trifluoro-2-heptanone and 3,3-difluoro-6,6-dimethyl-2-heptanone are inhibitors of acetylcholinesterase with Ki values of 16 X 10(-9) M and 1.6 X 10(-9) M, respectively. These fluoro ketones are 10(4)-10(5) times better as inhibitors than the corresponding methyl ketone. Since nucleophiles readily add to fluoro ketones, it is likely that these compounds inhibit acetylcholinesterase by formation of a stable hemiketal with the active-site serine residue. Fluoro ketone substrate analogues are also inhibitors of zinc metallo- and aspartylproteases. 2-Benzyl-4-oxo-5,5,5-trifluoropentanoic acid is an inhibitor of carboxypeptidase A (Ki = 2 X 10(-7) M). Trifluoromethyl ketone dipeptide analogues are good inhibitors of angiotensin converting enzyme. An analogue of pepstatin that contains a difluorostatone residue in place of statine has been prepared and found to be an extremely potent inhibitor of pepsin (Ki = 6 X 10(-11) M). The hydrated ketones are probably the inhibitory species since they are structural mimics of the tetrahedral intermediate that forms during the hydrolysis of peptide substrates.
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PMID:Fluoro ketone inhibitors of hydrolytic enzymes. 299 May 41

Dipeptide and tripeptide derivatives containing a statine residue were synthesized as inhibitors of human renin. ES-305, bis[(1-naphthyl)methyl]acetyl(BNMA)-histidyl-statine 2(S)-methylbutylamide was found to be a highly potent inhibitor of human renin with a Ki value of 1.7 X 10(-9) M. Dipeptide derivatives with the BNMA group at the N-terminal (BNMA-Val-Sta-isoleucinol [ES-313], BNMA-Leu-Sta-isoleucinol [ES-316], and BNMA-Nle-Sta-isoleucinol [ES-317]) had potencies against human renin that were similar to the potency of ES-305. All these dipeptide derivatives competitively inhibited human renin. The inhibitors were also potent against monkey renin but were less effective against renins from pig, goat, dog, rabbit, and rat. ES-305 had little effect on cathepsin D and pepsin at the concentration of 10(-5) M. The other derivatives showed detectable inhibition of cathepsin D (IC50, 10(-6) - 10(-7) M) and pepsin (10(-5) - 10(-6) M). All the compounds had little or no effect on trypsin, chymotrypsin, angiotensin converting enzyme, and urinary kallikrein at the concentration of 10(-5) M. Our results indicate that ES-305 is a highly potent and specific inhibitor of human renin. This compound is superior to other, previously described statine-containing renin inhibitors with respect to molecular size and enzyme specificity.
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PMID:Statine-containing dipeptide and tripeptide inhibitors of human renin. 308 74

An orally active renin inhibitor, ES 6864 (N-[(2R)-3-morpholinocarbonyl-2-(1-naphthylmethyl)propionyl]-(4- thiazolyl)-L-alanyl-cyclostatine-(2-morpholinoethyl)amide), was synthesized. ES 6864 was found to be a highly potent inhibitor of human renin with a Ki value of 7.3 x 10(-9) M. The compound competitively inhibited human renin. The inhibitor was also potent against monkey renin but was less effective against renins from pig, goat, dog, rabbit, and rat. ES 6864 did not inhibit cathepsin D, pepsin, trypsin, chymotrypsin, angiotensin converting enzyme, and urinary kallikrein at a concentration of 10(-5) M. ES 6864 was resistant to proteolytic actions of the enzymes in rat tissue homogenates (liver, kidney, pancreas, and small intestine). Oral administration of ES 6864 at 30 mg/kg to conscious, sodium-depleted marmosets produced a significant blood pressure reduction and almost complete inhibition of plasma renin activity, which persisted for 5 hours. Oral administration of ES 6864 also produced dose-related decreases of blood pressure in hog renin-infused rats, but the duration of action was much shorter than that in conscious marmosets. The parent compound in the blood following oral administration of ES 6864 to marmosets was confirmed directly by measuring the plasma concentration of ES 6864. These results enhance the possibility of developing renin inhibitors that can be used clinically.
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PMID:A highly potent and long-acting oral inhibitor of human renin. 313 6


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