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Chemical Structure| 188111-79-7 Chemical Structure| 188111-79-7

Structure of 188111-79-7

Chemical Structure| 188111-79-7

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Product Citations

Product Citations

Kitel, Radoslaw ; Surmiak, Ewa ; Borggrafe, Jan ; Kalinowska-Tluscik, Justyna ; Golik, Przemyslaw ; Czub, Miroslawa , et al.

Abstract: Here, we report the fragment-based drug discovery of potent and selective fragments that disrupt the Spire2-FMN2 but not the Spire1-FMN2 interaction. Hit fragments were identified in a differential scanning fluorimetry-based screen of an inhouse library of 755 compounds and subsequently validated in multiple orthogonal biophys. assays, including fluorescence polarization, microscale thermophoresis, and 1H-15N HSQC NMR. Extensive structure-activity relationships combined with mol. docking followed by chem. optimization led to the discovery of compound 13, which exhibits micromolar potency and high ligand efficiency (LE = 0.38). Therefore, this fragment represents a validated starting point for the future development of selective chem. probes targeting the Spire2-FMN2 interaction.

Alternative Products

Product Details of [ 188111-79-7 ]

CAS No. :188111-79-7
Formula : C10H20N2O2
M.W : 200.28
SMILES Code : C(=O)(OC(C)(C)C)N1CCC[C@H](C1)N
MDL No. :MFCD03094717

Safety of [ 188111-79-7 ]

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

Computational Chemistry of [ 188111-79-7 ] Show Less

Physicochemical Properties

Num. heavy atoms 14
Num. arom. heavy atoms 0
Fraction Csp3 0.9
Num. rotatable bonds 3
Num. H-bond acceptors 3.0
Num. H-bond donors 1.0
Molar Refractivity 59.3
TPSA ?

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

55.56 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.43
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

0.73
Log Po/w (WLOGP)?

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

0.96
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.

0.86
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

0.32
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.06

Water Solubility

Log S (ESOL):?

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

-1.34
Solubility 9.08 mg/ml ; 0.0453 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.

-1.48
Solubility 6.7 mg/ml ; 0.0335 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

-0.92
Solubility 24.1 mg/ml ; 0.12 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.

-7.0 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<1.0
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)

2.63

Application In Synthesis of [ 188111-79-7 ]

* 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 [ 188111-79-7 ]

[ 188111-79-7 ] Synthesis Path-Downstream   1~5

  • 1
  • [ 188111-79-7 ]
  • [ 166599-84-4 ]
  • [ 1030389-11-7 ]
YieldReaction ConditionsOperation in experiment
82% With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 20h; A.2.4 Synthesis of (R)-3-[(benzofuran-4-carbonyl)-amino]-piperidine-l- carboxylic acid tert-buty ester; A mixture of (R)-3-amino-l-N-Boc-piperidine (1 g), <strong>[166599-84-4]benzofuran-4-carboxylic acid</strong> (809 mg), PyBOP (2.6g), DIEA (1.96 mL) in dry DMF (10 mL) was stirred at RT under nitrogen for 20 h. The reaction mixture was diluted with EA, washed with water. The aqueous phase was extracted twice with EA, the combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated to yield a crude light brown oil. FC (EA/ n-heptane: 1/1 to EA) gave 1.41 g (82%) of the title compound as an oil. LC-MS: tR = 0.93 min; [M+H]+ = 345.
82% With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 20h; A mixture of (R)-3-amino-1-N-Boc-piperidine (1 g), <strong>[166599-84-4]benzofuran-4-carboxylic acid</strong> (809 mg), PyBOP (2.6 g), DIEA (1.96 mL) in dry DMF (10 mL) was stirred at RT under nitrogen for 20 h. The reaction mixture was diluted with EA, washed with water. The aqueous phase was extracted twice with EA, the combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated to yield a crude light brown oil. FC (EA/n-heptane: 1/1 to EA) gave 1.41 g (82%) of the title compound as an oil.LC-MS: tR=0.93 min; [M+H]+=345.
  • 2
  • [ 188111-79-7 ]
  • [ 68797-61-5 ]
  • (R)-tert-butyl 3-((5-bromo-6-chloropyrimidin-4-yl)amino)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
78% With diisopropylamine; In dichloromethane; at 0 - 20℃; for 1h; To a mixture of compound 18-1-1 (1 g, 5 mmol) in DCM (10 mL) was added DIPA (1.29 g, 10 mmol) and compound 18-1 (1.13 g, 5 mmol) at 0 C., and the reaction solution was stirred at r.t. for 1 h, followed by evaporation. The solvent was removed and the residue was purified by column chromatography to give compound 18-2 (1 g, Yield 78%). 1H NMR (400 MHz, CDCl3): delta ppm 1.39 (brs, 9H), 1.50-1.61 (m, 1H), 1.62-1.73 (m, 1H), 1.73-1.82 (m, 1H), 1.82-1.93 (m, 1H), 3.24-3.35 (m, 1H), 3.42-3.53 (m, 2H), 3.53-3.62 (m, 1H), 4.11 (d, J=2.65 Hz, 1H), 5.69 (m, 1H), 8.234-8.230 (m, 1H).
  • 3
  • [ 188111-79-7 ]
  • [ 3512-75-2 ]
  • C17H27N3O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
81% With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; DavePhos; at 100℃; for 16h;Inert atmosphere; Sealed tube; To a mixture of tris(dibenzylideneacetone)dipalladium(0) (CAS: 51364-51-3; 52 mg,0.057 nnno 1), 2-dicyclohexylphosphino-2 ?-(N,N-dimethylamino)biphenyl (CAS:213697-53-1; 41 mg, 0.104 mmol) and sodium tert-butoxide (154 mg, 1.6 mmol) in1,4-dioxane (5 mL) at rt and under N2 atmosphere, (R)-(-)-3-amino-1-Boc-piperidine(CAS: 188111-79-7; 0.23 mL, 1.2 mmol) and <strong>[3512-75-2]4-chloro-2,6-dimethylpyridine</strong> (0.127mL, 1 mmol) were added. The mixture was heated at 100 °C for 16 h in a sealed tube.Brine and DCM were added and the organic layer was separated, dried over MgSO4,filtered and evaporated under vacuum. The residue thus obtained was purified by flash column chromatography (Si02 amino functionalized; EtOAc in heptane, 0/100 to 100/0) and the desired fractions were concentrated in vacuo affording intermediate 16 as a yellow oil (248 mg, 81percent yield).
  • 4
  • [ 188111-79-7 ]
  • [ 1532-71-4 ]
  • tert-butyl (3R)-3-(isoquinolin-1-ylamino)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; at 100℃; for 12h;Inert atmosphere; 10524] WX042-1 (50.00 mg, 240.33 tmol, 1.00 eq), WXBB-3-1 (52.95 mg, 264.36 tmol, 1.10 eq), Pd2(dba)3 (22.01 mg, 24.03 tmol, 0.10 eq), BINAP (29.93 mg, 48.07 tmol, 0.20 eq) and t-BuONa (46.19 mg, 480.65 tmol, 2.00 eq) were added in the reaction flask, then anhydrous methylbenzene (10.00 mE) was added to the reaction flask. Under the nitrogen condition, the reaction liquid was stirred at 1000 C. for 12 h. Afier reaction, the reaction liquid was naturally cooled to room temperature, and filtered. The filtered cake was washed with ethyl acetate (20 mE). The filtrate was combined, concentrated under vacuum to obtain the crude. The crude was diluted with 20 mE of ethyl acetate and 20 mE of water. The pH of aqueous phase was adjusted with (2M) hydrochloric acid aqueous solution to 12. The mix- tare was layered, and then the aqueous phase was collected. The pH of aqueous phase was adjusted with solid sodium bicarbonate to 8, and ethyl acetate (20 mL*3) was added for extraction. The organic phase was combined, washed with saturated sodium chloride solution (10 mE), dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to obtain WX042-2.
  • 5
  • [ 188111-79-7 ]
  • [ 65550-81-4 ]
  • C16H24ClN3O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; at 90.0℃; for 18.0h; 10225] WXO14-1 (500.00 mg, 2.42 mmol, 1.00 eq) and compound WX1313-3-1 (533.51 mg, 2.66 mmol, 1.10 eq) were dissolved in methylbenzene (25 ml). Tris(dibenzylideneacetone)dipalladium (221.76 mg, 242.00 tmol, 0.10 eq), sodium tert-butoxide (349.08 mg,3.63 mmol,1.50 eq) and binaphthyl (I3INAP) (301.37 mg, 484.00 tmol, 0.20 eq) were added. The mixture was reacted at 90 C. for 18 h. Afier reaction, the reaction liquid was filtered through diatomite, the filtrate was washed with ethyl acetate (10 ml), and dried by rotary evaporation under vacuum. Ethyl acetate (50 ml) was added to residue. The resulting mixture was washed with water (10 ml), the organic phase was dried by rotary evaporation under vacuum, and the crude was purified by column chromatography (petroleum ether:ethyl acetate=30:1-10:1) to obtain the compound WXO14-2. ?H NMR (400 MHz, CDC13) oeppm: 7.76 (s, 1H), 7.22 (s, 1H), 4.79 (d, J=4.00 Hz, 1H), 3.98 (br, s, 1H), 3.30 (br, s, 3H),2.09 (s, 3H), 1.87-1.82 (m, 2H), 1.65-1.58 (m, 3H), 1.33 (s, 9H).
 

Historical Records

Technical Information

Categories

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[ 188111-79-7 ]

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