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Chemical Structure| 21653-40-7 Chemical Structure| 21653-40-7

Structure of Bz-Arg-PNA.HCl
CAS No.: 21653-40-7

Chemical Structure| 21653-40-7

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Product Citations

Product Citations

le Roux, Anandie ; Cloete, Stephanus J ; Petzer, Jacobus P ; Petzer, Anél ;

Abstract: Snakebite envenoming causes more than 130,000 deaths and more than 400,000 disabilities per year and has been classified as a priority Neglected Tropical Disease by the World Health Organization (WHO). While antivenom therapy remains the mainstay of snakebite treatment, small molecule therapeutics (SMTs) have been proposed as potential adjuncts to antivenom, particularly as oral treatment in the prehospital setting. Several SMTs have demonstrated efficacy in preclinical models of snakebite envenoming, with varespladib, a secreted phospholipase A2 (sPLA2) inhibitor, being granted orphan drug status for its potential to treat snakebite. The present study investigated the potential of four SMTs (e.g., varespladib, marimastat, nafamostat and dimercaprol) to neutralise toxic components present in the venom of southern African snake species. In vitro experimentation found that varespladib potently inhibited snake venom phospholipase A2 (svPLA2) activity in Bitis arietans (IC50 = 0.221 μM) and B. gabonica (IC50 = 0.276 μM). Marimastat exhibited potent inhibition of snake venom metalloproteinase (svMP) in several snake species with IC50 values ranging from 0.0042 to 3.06 μM, while dimercaprol, a metal chelator, was a lower potency svMP inhibitor with IC50 values ranging from 5.01 to 79.8 μM. Nafamostat proved to be an inhibitor of snake venom serine protease (svSP) in B. arietans (IC50 = 3.72 μM), B. gabonica (IC50 = 3.80 μM) and Causus rhombeatus (IC50 = 0.261 μM). These data demonstrate that SMTs are effective inhibitors of the relevant enzymes in several snake species and support the proposal that SMTs could be developed for therapeutic intervention in snakebite envenoming.

Keywords: Snakebite ; Varespladib ; Marimastat ; Nafamostat ; Dimercaprol ; Inhibition

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Product Details of [ 21653-40-7 ]

CAS No. :21653-40-7
Formula : C19H23ClN6O4
M.W : 434.88
SMILES Code : O=C(N[C@@H](CCCNC(N)=N)C(NC1=CC=C([N+]([O-])=O)C=C1)=O)C2=CC=CC=C2.[H]Cl
MDL No. :MFCD00063682
InChI Key :DEOKFPFLXFNAON-NTISSMGPSA-N
Pubchem ID :16219022

Safety of [ 21653-40-7 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Computational Chemistry of [ 21653-40-7 ] Show Less

Physicochemical Properties

Num. heavy atoms 30
Num. arom. heavy atoms 12
Fraction Csp3 0.21
Num. rotatable bonds 12
Num. H-bond acceptors 5.0
Num. H-bond donors 5.0
Molar Refractivity 117.39
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

165.92 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

0.0
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

2.31
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

2.21
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

1.16
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-0.57
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.02

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-3.5
Solubility 0.139 mg/ml ; 0.000319 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-5.43
Solubility 0.00161 mg/ml ; 0.00000369 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Moderately soluble
Log S (SILICOS-IT)?

SILICOS-IT: Fragmental method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-5.27
Solubility 0.00235 mg/ml ; 0.00000541 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Moderately soluble

Pharmacokinetics

GI absorption?

Gatrointestinal absorption: according to the white of the BOILED-Egg

Low
BBB permeant?

BBB permeation: according to the yolk of the BOILED-Egg

No
P-gp substrate?

P-glycoprotein substrate: SVM model built on 1033 molecules (training set)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

Yes
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

No
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

Yes
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

Yes
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

No
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

No
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-7.31 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

2.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

1.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

1.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.55

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

4.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

No; 1 violation:MW<2.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

3.19
 

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