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Chemical Structure| 105107-84-4 Chemical Structure| 105107-84-4

Structure of H-cis-4-PhenylThio-Pro-OH·HCl
CAS No.: 105107-84-4

Chemical Structure| 105107-84-4

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Product Citations

Product Citations

Kukułowicz, Jędrzej ; Siwek, Agata ; Wolak, Małgorzata ; Bröer, Angelika ; Yadav, Aditya ; Bröer, Stefan , et al.

Abstract: The sodium-dependent membrane transporter SLC6A15 (B0AT2) belongs to the SLC6 family, which comprises carriers of amino acids and monoamines. B0AT2 is expressed in the central nervous system (CNS), including the glutaminergic and GABAergic system. SLC6A15 supplies neurons with neutral amino acids. Its main substrates, branched-chain amino acids, and proline serve for glutamate biosynthesis, whereas silencing of B0AT2 leads to lower levels of neuronal glutamate. Recent research revealed that polymorphisms in the vicinity of slc6a15 are associated with major depressive disorder and anxiety. Mouse B0AT2 knockouts, by contrast, showed an antianxiety feature. Applying computational tools, we constructed models of B0AT2. Their structure was discussed extensively, enabling insight into the determinants of transport mechanism and substrate selectivity. Understanding the molecular basis of the B0AT2 inhibition by loratadine led to the discovery of a new inhibitor that is tiagabine, an anticonvulsant drug prescribed off-label in the treatment of anxiety and possessing antidepressant features. The results showed that tiagabine appears to have a higher affinity to the transporter than loratadine, which is the most potent inhibitor to date. Our findings support the development of new B0AT2 inhibitors that could be useful for investigating their therapeutic relevance, while the identification of tiagabine as a novel SLC6A15 inhibitor adds a new dimension to the pharmacological complexity of this drug.

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Product Details of [ 105107-84-4 ]

CAS No. :105107-84-4
Formula : C11H14ClNO2S
M.W : 259.75
SMILES Code : O=C(O)[C@H]1NC[C@@H](SC2=CC=CC=C2)C1.[H]Cl
MDL No. :MFCD11109939
InChI Key :XXNAGGDFBCTLQA-IYPAPVHQSA-N
Pubchem ID :46705431

Safety of [ 105107-84-4 ]

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

Computational Chemistry of [ 105107-84-4 ] Show Less

Physicochemical Properties

Num. heavy atoms 16
Num. arom. heavy atoms 6
Fraction Csp3 0.36
Num. rotatable bonds 3
Num. H-bond acceptors 3.0
Num. H-bond donors 2.0
Molar Refractivity 70.73
TPSA ?

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

74.63 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

0.52
Log Po/w (WLOGP)?

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

2.01
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.

-0.36
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

1.5
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.73

Water Solubility

Log S (ESOL):?

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

-1.86
Solubility 3.61 mg/ml ; 0.0139 mol/l
Class?

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

Very soluble
Log S (Ali)?

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

-1.66
Solubility 5.71 mg/ml ; 0.022 mol/l
Class?

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

Very 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

-2.59
Solubility 0.669 mg/ml ; 0.00258 mol/l
Class?

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

Soluble

Pharmacokinetics

GI absorption?

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

High
BBB permeant?

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

Yes
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

No
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

No
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

No
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.

-7.52 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

0.0
Egan?

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

0.0
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

0.0
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

0.0 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<0.0
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)

3.04

Application In Synthesis of [ 105107-84-4 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 105107-84-4 ]

[ 105107-84-4 ] Synthesis Path-Downstream   1~2

  • 1
  • [ 83623-88-5 ]
  • [ 105107-84-4 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; In 1,4-dioxane; at 20℃; for 2.0h; (Comparative Example 5) The compound in Comparative Example 5 was synthesized according to the method described in the Patent document 2: ethyl(2S,4S)-1-tert-butoxycarbonyl-4-(phenylsulfanyl)pyrrolidine-2-carboxylate, prepared from ethyl(2S,4R)-1-tert-butoxycarbonyl-4-(4-toluenesulphonyloxy)-pyrrolidine-2-carboxylate and thiophenol, was hydrolyzed with sodium hydroxide and then the product was treated with 4 M hydrochloric acid in dioxane at room temperature for 2 hours to afford the deprotected compound.
  • 2
  • [ 105107-84-4 ]
  • [ 74654-91-4 ]
  • [ 81872-10-8 ]
YieldReaction ConditionsOperation in experiment
With water; sodium hydrogencarbonate; sodium carbonate; In acetone; at 15 - 20℃;pH 8 - 10;Large scale reaction; General procedure: The (S)-amino acid (10.0 g) was dissolved in H2O (300 ml) and Na2CO3 (2.0 equiv) and NaHCO3 (1.0 equiv) were added at rt, with stirring, to give a clear solution. Acetone (4.0 vol, with respect to the amino acid) was added and the slightly turbid solution was cooled in an ice water bath to 15-20 C. Cbz-Cl (1.25 equiv) was added slowly, with stirring, and the reaction mixture allowed to warm to rt. After stirring for an additional 3 h at rt the mixture was extracted with Et2O (50 ml). To the aqueous phase was slowly added aqueous HCl to give a pH of 2. The resulting oil was extracted into EtOAc (150 ml) and this was washed with H2O (100 ml) and then concentrated in vacuo to give the N-Cbz amino acid as a white solid, see Table 1.
 

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