Identification

Name
Remikiren
Accession Number
DB00212  (APRD00163)
Type
Small Molecule
Groups
Experimental
Description

Remikiren is an orally active, high specificity renin inhibitor.

Structure
Thumb
Synonyms
Not Available
External IDs
Ro 42-5892 / RO-42-5892
Categories
UNII
LC7FBL96A4
CAS number
126222-34-2
Weight
Average: 630.838
Monoisotopic: 630.345106042
Chemical Formula
C33H50N4O6S
InChI Key
UXIGZRQVLGFTOU-VQXQMPIVSA-N
InChI
InChI=1S/C33H50N4O6S/c1-33(2,3)44(42,43)20-25(16-22-10-6-4-7-11-22)31(40)37-28(18-26-19-34-21-35-26)32(41)36-27(17-23-12-8-5-9-13-23)30(39)29(38)24-14-15-24/h4,6-7,10-11,19,21,23-25,27-30,38-39H,5,8-9,12-18,20H2,1-3H3,(H,34,35)(H,36,41)(H,37,40)/t25-,27+,28+,29+,30-/m1/s1
IUPAC Name
(2S)-2-{[(2S)-2-benzyl-1-hydroxy-3-(2-methylpropane-2-sulfonyl)propylidene]amino}-N-[(2S,3R,4S)-1-cyclohexyl-4-cyclopropyl-3,4-dihydroxybutan-2-yl]-3-(1H-imidazol-5-yl)propanimidic acid
SMILES
[H][C@@](CC1=CC=CC=C1)(CS(=O)(=O)C(C)(C)C)C(O)=N[C@@]([H])(CC1=CN=CN1)C(O)=N[C@@]([H])(CC1CCCCC1)[C@@]([H])(O)[C@@]([H])(O)C1CC1

Pharmacology

Indication

For the treatment of hypertension and heart failure

Pharmacodynamics

Remikiren is an orally available renin inhibitor with an established blood pressure-lowering effect in patients with essential hypertension. No data are available on the renal effects of remikiren in humans. In patients with essential hypertension, a single oral dose of remikiren can induce a renal vasodilation, without affecting the GFR and despite a significant decrease in blood pressure. This systemic and renal hemodynamic response is more pronounced in case of a more activated renin-angiotensin system.

Mechanism of action

Several in vivo experiments have shown that remikiren is specific for renin and does not decrease arterial pressure by an unrelated mechanism.

TargetActionsOrganism
ARenin
inhibitor
Human
Absorption

Absorbed following oral administration.

Volume of distribution
Not Available
Protein binding

83%

Metabolism
Not Available
Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AcebutololRemikiren may increase the hypotensive activities of Acebutolol.
AceclofenacThe therapeutic efficacy of Remikiren can be decreased when used in combination with Aceclofenac.
AcemetacinThe therapeutic efficacy of Remikiren can be decreased when used in combination with Acemetacin.
Acetylsalicylic acidThe therapeutic efficacy of Remikiren can be decreased when used in combination with Acetylsalicylic acid.
AlclofenacThe therapeutic efficacy of Remikiren can be decreased when used in combination with Alclofenac.
AlfuzosinAlfuzosin may increase the hypotensive activities of Remikiren.
AliskirenRemikiren may increase the hypotensive activities of Aliskiren.
AlminoprofenThe therapeutic efficacy of Remikiren can be decreased when used in combination with Alminoprofen.
AlprenololRemikiren may increase the hypotensive activities of Alprenolol.
AmbrisentanRemikiren may increase the hypotensive activities of Ambrisentan.
Food Interactions
Not Available

References

General References
  1. Clozel JP, Fischli W: Discovery of remikiren as the first orally active renin inhibitor. Arzneimittelforschung. 1993 Feb;43(2A):260-2. [PubMed:8498974]
  2. Richter WF, Whitby BR, Chou RC: Distribution of remikiren, a potent orally active inhibitor of human renin, in laboratory animals. Xenobiotica. 1996 Mar;26(3):243-54. [PubMed:8730917]
External Links
KEGG Compound
C07465
PubChem Compound
6324659
PubChem Substance
46507286
ChemSpider
4884377
BindingDB
50077669
ChEMBL
CHEMBL31601
Therapeutic Targets Database
DAP001220
PharmGKB
PA164774779
HET
REM
Wikipedia
Remikiren
ATC Codes
C09XA01 — Remikiren
PDB Entries
3d91

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
logP3.9Not Available
Caco2 permeability-6.13ADME Research, USCD
Predicted Properties
PropertyValueSource
Water Solubility0.0128 mg/mLALOGPS
logP3.56ALOGPS
logP3.22ChemAxon
logS-4.7ALOGPS
pKa (Strongest Acidic)5.47ChemAxon
pKa (Strongest Basic)6.49ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count9ChemAxon
Hydrogen Donor Count5ChemAxon
Polar Surface Area168.46 Å2ChemAxon
Rotatable Bond Count16ChemAxon
Refractivity170.64 m3·mol-1ChemAxon
Polarizability68.82 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.8744
Blood Brain Barrier-0.8746
Caco-2 permeable-0.8957
P-glycoprotein substrateSubstrate0.7043
P-glycoprotein inhibitor INon-inhibitor0.6427
P-glycoprotein inhibitor IINon-inhibitor0.9732
Renal organic cation transporterNon-inhibitor0.8832
CYP450 2C9 substrateNon-substrate0.5243
CYP450 2D6 substrateNon-substrate0.7775
CYP450 3A4 substrateSubstrate0.5695
CYP450 1A2 substrateNon-inhibitor0.8245
CYP450 2C9 inhibitorNon-inhibitor0.6456
CYP450 2D6 inhibitorNon-inhibitor0.8548
CYP450 2C19 inhibitorNon-inhibitor0.6534
CYP450 3A4 inhibitorInhibitor0.8648
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.6298
Ames testNon AMES toxic0.9132
CarcinogenicityNon-carcinogens0.7601
BiodegradationNot ready biodegradable0.9754
Rat acute toxicity2.5600 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9958
hERG inhibition (predictor II)Non-inhibitor0.5881
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as histidine and derivatives. These are compounds containing cysteine or a derivative thereof resulting from reaction of cysteine at the amino group or the carboxy group, or from the replacement of any hydrogen of glycine by a heteroatom.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
Histidine and derivatives
Alternative Parents
N-acyl-alpha amino acids and derivatives / Alpha amino acid amides / Benzene and substituted derivatives / Fatty amides / Sulfones / Imidazoles / Heteroaromatic compounds / Secondary carboxylic acid amides / Secondary alcohols / 1,2-diols
show 6 more
Substituents
Histidine or derivatives / N-acyl-alpha amino acid or derivatives / Alpha-amino acid amide / Monocyclic benzene moiety / Fatty amide / Fatty acyl / Benzenoid / Azole / Imidazole / Heteroaromatic compound
show 19 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Receptor binding
Specific Function
Renin is a highly specific endopeptidase, whose only known function is to generate angiotensin I from angiotensinogen in the plasma, initiating a cascade of reactions that produce an elevation of b...
Gene Name
REN
Uniprot ID
P00797
Uniprot Name
Renin
Molecular Weight
45057.125 Da
References
  1. van Paassen P, Navis GJ, De Jong PE, De Zeeuw D: Pretreatment renal vascular tone predicts the effect of specific renin inhibition on natriuresis in essential hypertension. Eur J Clin Invest. 1999 Dec;29(12):1019-26. [PubMed:10583449]
  2. MacFadyen RJ, Jones CR, Doig JK, Birnbock H, Reid JL: Responses to an orally active renin inhibitor, remikiren (Ro 42-5892), after controlled salt depletion in humans. J Cardiovasc Pharmacol. 1995 Mar;25(3):347-53. [PubMed:7769797]
  3. Kiowski W, Beermann J, Rickenbacher P, Haemmerli R, Thomas M, Burkart F, Meinertz T: Angiotensinergic versus nonangiotensinergic hemodynamic effects of converting enzyme inhibition in patients with chronic heart failure. Assessment by acute renin and converting enzyme inhibition. Circulation. 1994 Dec;90(6):2748-56. [PubMed:7994817]
  4. Hilgers KF, Fischli W, Veelken R, Mann JF: Vascular renin in the guinea pig. Suppression by the renin inhibitor remikiren. Hypertension. 1994 Jun;23(6 Pt 2):861-4. [PubMed:8206619]
  5. Clozel JP, Fischli W: Comparative effects of three different potent renin inhibitors in primates. Hypertension. 1993 Jul;22(1):9-17. [PubMed:8319997]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]

Drug created on June 13, 2005 07:24 / Updated on November 02, 2018 04:39