CV 5975
CV 5975 is an orally active angiotensin converting enzyme (ACE) competitive inhibitor with a rabbit lung ACE IC50 of 3.1 nM and Ki values of 2.6 nM. CV 5975 inhibits ACE in plasma, aorta, kidney, and brain, intensifying inhibition with repeated administration. CV 5975 inhibits Angiotensin I (HY-P1032)-induced pressor responses and ileum contraction, and augments bradykinin-induced ileum contraction and depressor responses. CV 5975 reduces blood pressure via ACE-independent mechanisms, with sustained action across multiple hypertensive and normotensive animal models, intensified by repeated dosing or Hydrochlorothiazide (HY-B0252) co-administration. CV 5975 can be used for the research of hypertension.
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- No. CAS: 100277-62-1
- Fòrmula: C22H31N3O5S
- Peso molecular:449.56
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Almacenamiento:
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Chemical Information
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Actividad biológica
Descripciòn
IC50 & Target
[1]|
ACE |
In Vitro
CV 5975 (40 g; 3.5-29 h) Chemoenzymatic kinetic resolution with lipase PN produces (R)-4 (64% ee) that is converted to CV-5975 via mesylation, SN2 reaction, and deprotection, with an overall 25% yield from (R)-4[1].
CV 5975 (40 g; 48 h) Baker's yeast-mediated asymmetric reduction of α-oxoester 3 produces (R)-4 (61% ee) in 46% yield, which is suitable for the synthesis of CV-5975[1].
CV 5975 (10-8 M; 60 min) potently inhibits crude angiotensin converting enzyme from albino male rabbit lungs with an IC50 of 3.1 × 10-9 M, demonstrating far greater potency than its three stereoisomers[2].
CV 5975 (20 min) potently and competitively inhibits partially purified rabbit lung ACE, with an IC50 of 3.1 × 10-9 M, a Ki of 2.6 × 10-9 M, and a high-affinity steady-state Ki* of 4.4 × 10-12 M[4].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
In Vivo
CV 5975 (10 mg/kg; p.o.; single dose) produces a mild, significant hypotensive effect in normotensive Wistar Kyoto rats that persists for 10 hours[3].
CV 5975 (1-10 mg/kg; p.o.; daily for 2 weeks) exerts dose-dependent, sustained antihypertensive effects in spontaneously hypertensive rats, with intensified potency and duration upon repeated dosing, and produces marked, tissue-wide ACE inhibition that correlates with blood pressure reduction[3].
CV 5975 (1-10 mg/kg; p.o.; single dose) produces a potent, long-lasting, dose-dependent antihypertensive effect in 2-kidney, 1-clip renal hypertensive rats, with a maximum blood pressure reduction of 65 mmHg that persists for over 24 hours at the 10 mg/kg oral dose[3].
CV 5975 (1-10 mg/kg; p.o.; single dose) exerts a dose-dependent antihypertensive effect in 1-kidney, 1-clip renal hypertensive rats, with a significant blood pressure reduction lasting over 10 hours at the 10 mg/kg oral dose[3].
CV 5975 (1-10 mg/kg; p.o.; single dose; daily for 2 weeks) produces a mild, dose-dependent antihypertensive effect in hyporeninemic DOCA/salt hypertensive rats, with no enhanced efficacy upon repeated daily dosing[3].
CV 5975 (0.3-1 mg/kg; p.o.; single dose) produces a long-lasting antihypertensive effect in 2-kidney, 1-clip renal hypertensive dogs, reducing systolic and diastolic blood pressure by approximately 40 mmHg at the 1 mg/kg dose[3].
CV 5975 (0.3-1 mg/kg; p.o.) potently inhibits Angiotensin I-induced pressor responses in normotensive beagle dogs at 0.3 and 1 mg/kg p.o., with over 90% inhibition and longer lasting effects than enalapril[4].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:Sprague-Dawley (male, 300-400 g)[2]
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Dosage:0.3 mg/kg (i.v.); 3 mg/kg (p.o.)
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Administration:i.v. or p.o.; single dose
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Result:Inhibited angiotensin I-induced pressor responses by 96% at 10 minutes, 99% at 30 minutes, 93% at 60 minutes, and 91% at 120 minutes after intravenous 0.3 mg/kg administration.
Exhibited the longest duration of ACE inhibition among tested piperidyl derivatives, with recovery to 50% of control taking over 4 hours after intravenous 0.3 mg/kg administration.
Inhibited angiotensin I-induced pressor responses by 70% at 20 minutes, 84% at 1 hour, 91% at 3 hours, 88% at 5 hours, and 84% at 7 hours after oral 3 mg/kg administration.
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Animal Model:Wistar Kyoto rats (male, 20 to 22 weeks old)[3]
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Dosage:10 mg/kg
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Administration:p.o.; single dose
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Result:Slightly but significantly reduced mean arterial blood pressure, with maximum reductions of 9 mmHg at 5 hr, 8 mmHg at 7 hr, and 10 mmHg at 10 hr.
Returned blood pressure to pre-drug levels by 24 hr post-administration.
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Animal Model:Spontaneously hypertensive rats (male, 20 to 22 weeks old)[3]
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Dosage:1 mg/kg; 3 mg/kg; 10 mg/kg
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Administration:p.o.; single dose; daily for 2 weeks
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Result:Reduced blood pressure dose-dependently by 10 to 35 mmHg, with maximum effects at 5 to 10 hr that lasted more than 24 hr.
Intensified antihypertensive potency and duration upon repeated dosing, with maximum effects observed on day 7; 1 week after treatment cessation, blood pressure remained significantly lower than controls (202 mmHg at 1 mg/kg, 203 mmHg at 3 mg/kg, 202 mmHg at 10 mg/kg) and returned to control levels by 2 weeks post-cessation.
Inhibited ACE activity in all tested tissues (plasma, aorta, kidney, lung, brain) after repeated daily dosing for 1 week.
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Animal Model:Wistar rats (male, 6 weeks old initially, used 4 to 6 weeks after 2-kidney, 1-clip renal hypertension surgery, systolic blood pressure 160 to 240 mmHg)[3]
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Dosage:1 mg/kg; 3 mg/kg; 10 mg/kg
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Administration:p.o.; single dose
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Result:Caused a dose-related, marked, sustained decrease in blood pressure; the maximum effect of ~65 mmHg was seen at 7 to 10 hr post-dose, and blood pressure remained below pre-drug levels for more than 24 hr.
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Animal Model:Wistar rats (male, 6 weeks old initially, used 4 to 6 weeks after 1-kidney, 1-clip renal hypertension surgery, systolic blood pressure 160 to 240 mmHg)[3]
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Dosage:1 mg/kg; 3 mg/kg; 10 mg/kg
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Administration:p.o.; single dose
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Result:Reduced blood pressure dose-dependently; at 10 mg/kg, the effect was observed from 3 hr post-dose and blood pressure remained lower than control levels for more than 10 hr.
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Animal Model:Wistar rats (male, 6 weeks old initially, used 4 to 6 weeks after hyporeninemic DOCA/salt hypertension surgery, systolic blood pressure 160 to 240 mmHg)[3]
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Dosage:1 mg/kg; 3 mg/kg; 10 mg/kg
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Administration:p.o.; single dose; daily for 2 weeks
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Result:Induced a mild, consistent antihypertensive effect after single administration.
Reduced arterial blood pressure in a dose-related manner with repeated daily dosing, with no intensification of effect; the antihypertensive effect disappeared within 24 hr after each dose cessation.
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Animal Model:Beagle dogs (male, 13 to 16 kg, used 2 to 5 weeks after 2-kidney, 1-clip renal hypertension surgery)[3]
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Dosage:0.3 mg/kg; 1 mg/kg
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Administration:p.o.; single dose
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Result:Induced a modest, long-lasting reduction in systemic blood pressure within 1 hr of administration, with effects persisting for more than 10 hr.
Lowered both systolic and diastolic blood pressure by about 40 mmHg at 1 mg/kg, and heart rate tended to increase (not statistically significant).
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Animal Model:Sprague-Dawley rats (male, 300-400 g)[4]
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Dosage:0.03 mg/kg (i.v.); 0.3 mg/kg (i.v.); 3 mg/kg (p.o.); 10 mg/kg (p.o.)
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Administration:i.v. or p.o.
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Result:Induced maximum inhibition of angiotensin I (A-I) pressor response at 5 min, with longer lasting effects than enalaprilat at 0.03 mg/kg i.v.
Had a half-time of recovery (T1/2) of about 5 hr, and an ID50 of 0.07 mg/kg i.v. over a 7 hr observation period at 0.3 mg/kg i.v.
Augmented bradykinin (BK)-induced depressor response to -31.6 mmHg at 1 hr, -32.0 mmHg at 3 hr, -28.6 mmHg at 5 hr, and -24.8 mmHg at 7 hr at 3 mg/kg p.o.
Had an inhibitory effect on A-I pressor response lasting over 24 hr, with an ID50 of 1.8 mg/kg p.o. over a 24 hr observation period at 10 mg/kg p.o.
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Animal Model:Beagle dogs (either sex, 13-15 kg)[4]
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Dosage:0.3 mg/kg; 1 mg/kg
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Administration:p.o.
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Result:Inhibited angiotensin I (A-I)-induced pressor response by over 90%, with prolonged inhibitory action compared to enalapril at 0.3 mg/kg p.o.
Inhibited A-I-induced pressor response by over 90%, with duration of action extending beyond 24 hr, while enalapril's effect at 1 mg/kg p.o. was no longer evident at 24 hr at 1 mg/kg p.o.
Chemical Information
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No. CAS 100277-62-1
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Peso molecular 449.56
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Fòrmula C22H31N3O5S
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SMILES
OC(CN1C2=CC=CC=C2SC[C@@H](C1=O)N[C@H](C(O)=O)CCCCC3CCNCC3)=O
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Envío
Room temperature in continental US; may vary elsewhere.
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Almacenamiento
Please store the product under the recommended conditions in the Certificate of Analysis.
Pureza y Documentación
Referencias
[1]. Kori M, et al. An improved synthesis of the new angiotensin converting enzyme inhibitor CV-5975 via a chemoenzymatic process. Chem Pharm Bull (Tokyo). 1987 Jun;35(6):2319-26. [Content Brief]
[2]. Inada Y, et al. (R)-3-[(S)-1-carboxy-5-(4-piperidyl)pentyl]amino-4-oxo-2,3,4,5- tetrahydro-1,5-benzothiazepine-5-acetic acid (CV-5975): a new potent and long-lasting inhibitor of angiotensin converting enzyme. Jpn J Pharmacol. 1988;47(2):135-141. [Content Brief]
[3]. Inada Y, et al. Antihypertensive action of a new angiotensin converting enzyme inhibitor, (R)-3-[(S)-1-carboxy-5-(4-piperidyl)pentyl]amino-4-oxo-2,3,4,5-tetr ahy dro-1,5-benzothiazepine-5-acetic acid (CV-5975), in various hypertensive models. Jpn J Pharmacol. 1988;47(3):311-322. [Content Brief]
[4]. Inada Y, et al. Inhibition of angiotensin converting enzyme by (R)-3-[(S)-1-carboxy-5-(4-piperidyl)pentyl]amino-4-oxo-2,3,4,5-tetra- hydro-1,5-benzothiazepine-6-acetic acid (CV-5975), a non-sulfhydryl compound. Jpn J Pharmacol. 1988;48(3):323-330. [Content Brief]
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
CV 5975 Related Classifications
HY-182407 Related Classifications
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