AZIMILIDE


Synonyms	Azimilide
Status
Molecule Category	UNKNOWN
UNII	74QU6P2934


Active Pharmaceutical Ingredients Bioactive chemicals	Exact Similarity SubStructure	Threshold (%) >= 70

Structure


InChI Key	MREBEPTUUMTTIA-PCLIKHOPSA-N
Smiles	CN1CCN(CCCCN2C(=O)CN(/N=C/c3ccc(-c4ccc(Cl)cc4)o3)C2=O)CC1
InChI	InChI=1S/C23H28ClN5O3/c1-26-12-14-27(15-13-26)10-2-3-11-28-22(30)17-29(23(28)31)25-16-20-8-9-21(32-20)18-4-6-19(24)7-5-18/h4-9,16H,2-3,10-15,17H2,1H3/b25-16+

Physicochemical Descriptors

Property Name	Value
Molecular Formula	C23H28ClN5O3
Molecular Weight	457.96
AlogP	3.23
Hydrogen Bond Acceptor	6.0
Hydrogen Bond Donor	0.0
Number of Rotational Bond	8.0
Polar Surface Area	72.6
Molecular species	NEUTRAL
Aromatic Rings	2.0
Heavy Atoms	32.0

Reference

Journal : J. Med. Chem.

Title : Toward a pharmacophore for drugs inducing the long QT syndrome: insights from a CoMFA study of HERG K(+) channel blockers.

PubMed ID : 12190308

DOI : 10.1021/jm0208875

Year : 2002

Volume : 45

Issue : 18

First Page : 3844

Last Page : 3853

Authors : Cavalli A, Poluzzi E, De Ponti F, Recanatini M.

Abstract : In this paper, we present a pharmacophore for QT-prolonging drugs, along with a 3D QSAR (CoMFA) study for a series of very structurally variegate HERG K(+) channel blockers. The blockade of HERG K(+) channels is one of the most important molecular mechanisms through which QT-prolonging drugs increase cardiac action potential duration. Since QT prolongation is one of the most undesirable side effects of drugs, we first tried to identify the minimum set of molecular features responsible for this action and then we attempted to develop a quantitative model correlating the 3D stereoelectronic characteristics of the molecules with their HERG blocking potency. Having considered an initial set of 31 QT-prolonging drugs for which the HERG K(+) channel blocking activity was measured on mammalian transfected cells, we started the construction of a theoretical screening tool able to predict whether a new molecule can interact with the HERG channel and eventually induce the long QT syndrome. This in silico tool might be useful in the design of new drug candidates devoid of the physicochemical features likely to cause the above-mentioned side effect.

Reference

Journal : Bioorg. Med. Chem. Lett.

Title : The pharmacophore hypotheses of I(Kr) potassium channel blockers: novel class III antiarrhythmic agents.

PubMed ID : 15324906

DOI : 10.1016/j.bmcl.2004.06.070

Year : 2004

Volume : 14

Issue : 18

First Page : 4771

Last Page : 4777

Authors : Du LP, Tsai KC, Li MY, You QD, Xia L.

Abstract : Predictive pharmacophore models were developed for a large series of I(Kr) potassium channel blockers as class III antiarrhythmic agents using HypoGen in Catalyst software. The pharmacophore hypotheses were generated using a training set consisting of 34 compounds carefully selected from documents. Their biological data, expressed as IC(50), spanned from 1.5 nM to 2.8 mM with 7 orders difference. The most predictive hypothesis (Hypo1), consisting of four features (one positive ionizable feature, two aromatic rings and one hydrophobic group), had a best correlation coefficient of 0.825, a lowest rms deviation of 1.612, and a highest cost difference (null cost-total cost) of 77.552, which represents a true correlation and a good predictivity. The hypothesis Hypo1 was then validated by a test set consisting of 21 compounds and by a cross-validation of 95% confidence level with randomizing the data using CatScramble program. Accordingly, our model has strong predictivity to identify structural diverse I(Kr) potassium channel blockers with desired biological activity by virtual screening

Reference

Journal : Bioorg. Med. Chem. Lett.

Title : Molecular hybridization, synthesis, and biological evaluation of novel chroman I(Kr) and I(Ks) dual blockers.

PubMed ID : 19185489

DOI : 10.1016/j.bmcl.2009.01.022

Year : 2009

Volume : 19

Issue : 5

First Page : 1477

Last Page : 1480

Authors : Du L, Li M, Yang Q, Tang Y, You Q, Xia L.

Abstract : The combination of I(Kr) and I(Ks) blockade could lead to synergistic and safe class III anti-arrhythmic effect with the enhanced efficacy and reduced risk. On the rationale of structural hybridization of azimilide and HMR-1556, a novel series of I(Kr) and I(Ks) dual blockers were designed, synthesized and evaluated in vitro. One compound, 3r (CPUY11018), deserves further evaluation for its potent anti-arrhythmic activity and favorable cardiovascular profile.

Reference

Journal : Bioorg. Med. Chem. Lett.

Title : Molecular hybridization, synthesis, and biological evaluation of novel chroman I(Kr) and I(Ks) dual blockers.

PubMed ID : 19185489

DOI : 10.1016/j.bmcl.2009.01.022

Year : 2009

Volume : 19

Issue : 5

First Page : 1477

Last Page : 1480

Authors : Du L, Li M, Yang Q, Tang Y, You Q, Xia L.

Reference

Journal : Eur. J. Med. Chem.

Title : GRIND-based 3D-QSAR and CoMFA to investigate topics dominated by hydrophobic interactions: the case of hERG K+ channel blockers.

PubMed ID : 19110341

DOI : 10.1016/j.ejmech.2008.11.009

Year : 2009

Volume : 44

Issue : 5

First Page : 1926

Last Page : 1932

Authors : Ermondi G, Visentin S, Caron G.

Abstract : The study compares GRIND-based 3D-QSAR and CoMFA [A. Cavalli, E. Poluzzi, F. De Ponti, M. Recanatini, J. Med. Chem, 45(2002), 3844-53] to investigate a biological topic dominated by hydrophobic interactions, e.g. hERG K(+) channel blocking activity. As expected, models are found by both methods and there is a fine agreement between statistical and graphical results as well. However, a closer inspection revealed that failures in the prediction of hERG blocking activity for lipophilic compounds were registered for both methods. The study explores the reasons for these failures which are strongly dependent on the chosen method, and gives some suggestions to handle with these topics.

Reference

Journal : Eur. J. Med. Chem.

Title : Predicting hERG activities of compounds from their 3D structures: development and evaluation of a global descriptors based QSAR model.

PubMed ID : 21185626

DOI : 10.1016/j.ejmech.2010.11.042

Year : 2011

Volume : 46

Issue : 2

First Page : 618

Last Page : 630

Authors : Sinha N, Sen S.

Abstract : A QSAR based predictive model of hERG activity in terms of 'global descriptors' has been developed and evaluated. The QSAR was developed by training 77 compounds covering a wide range of activities and was validated based on an external 'test set' of 80 compounds using neural network method. Statistical parameters and examination of enrichment factor indicated the effectiveness of the present model. Randomization test demonstrated the robustness of the model and cross-validation test further validated the QSAR. Domain of applicability test indicated to the high degree of reliability of the predicted results. Satisfactory performance in classifying compounds into 'active' and 'inactive' groups was also obtained. The cases where the QSAR failed, the possible sources of errors have been discussed.

Assay Description	Organism	Bioactivity
K+ channel blocking activity in Chinese hamster ovary cells expressing HERG Kv11.1	None	560.0 nM
Inhibitory concentration against IKr potassium channel	None	400.0 nM
Inhibition of ERG in guinea pig ventricular myocytes assessed as blockade of rapid delayed rectifier potassium current by whole cell patch-clamp technique	Cavia porcellus	180.0 nM
Inhibition of KVLQT1/minK in guinea pig ventricular myocytes assessed as blockade of slow delayed rectifier potassium current by whole cell patch-clamp technique	Cavia porcellus	240.0 nM
Inhibition of human ERG in MCF7 cells	Homo sapiens	562.34 nM
Inhibition of human ERG	Homo sapiens	562.34 nM

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Cross References

Resources	Reference
ChEBI	34545
ChEMBL	CHEMBL123558
FDA SRS	74QU6P2934
Guide to Pharmacology	2588
KEGG	C13777
PubChem	60939
SureChEMBL	SCHEMBL26354
ZINC	ZINC000021983255

CONTENTS

Structure
Chemical and Physical Properties
Related Entries