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Chemical Structure| 1591-37-3 Chemical Structure| 1591-37-3

Structure of 1591-37-3

Chemical Structure| 1591-37-3

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Product Citations

Product Citations

Shifali Shishodia ; Raymundo Nuñez ; Brayden P. Strohmier ; Karina L. Bursch ; Christopher J. Goetz ; Michael D. Olp , et al.

Abstract: PBRM1 is a subunit of the PBAF chromatin remodeling complex that uniquely contains six bromodomains. PBRM1 can operate as a tumor suppressor or tumor promoter. PBRM1 is a tumor promoter in prostate cancer, contributing to migratory and immunosuppressive phenotypes. Selective chemical probes targeting PBRM1 bromodomains are desired to elucidate the association between aberrant PBRM1 chromatin binding and cancer pathogenesis and the contributions of PBRM1 to immunotherapy. Previous PBRM1 inhibitors unselectively bind SMARCA2 and SMARCA4 bromodomains with nanomolar potency. We used our protein-detected NMR screening pipeline to screen 1968 fragments against the second PBRM1 bromodomain, identifying 17 hits with Kd values from 45 μM to >2 mM. Structure–activity relationship studies on the tightest-binding hit resulted in nanomolar inhibitors with selectivity for PBRM1 over SMARCA2 and SMARCA4. These chemical probes inhibit the association of full-length PBRM1 to acetylated histone peptides and selectively inhibit growth of a PBRM1-dependent prostate cancer cell line.

Alternative Products

Product Details of [ 1591-37-3 ]

CAS No. :1591-37-3
Formula : C8H8N2O
M.W : 148.16
SMILES Code : COC1=CC=CC(N)=C1C#N
MDL No. :MFCD09745275
InChI Key :LBVLXRZXEOPYDW-UHFFFAOYSA-N
Pubchem ID :12715714

Safety of [ 1591-37-3 ]

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

Computational Chemistry of [ 1591-37-3 ] Show Less

Physicochemical Properties

Num. heavy atoms 11
Num. arom. heavy atoms 6
Fraction Csp3 0.12
Num. rotatable bonds 1
Num. H-bond acceptors 2.0
Num. H-bond donors 1.0
Molar Refractivity 42.05
TPSA ?

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

59.04 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.5
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

1.48
Log Po/w (WLOGP)?

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

1.16
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.

0.51
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

1.07
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.14

Water Solubility

Log S (ESOL):?

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

-2.03
Solubility 1.39 mg/ml ; 0.00936 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.

-2.33
Solubility 0.698 mg/ml ; 0.00471 mol/l
Class?

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

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

-2.23
Solubility 0.868 mg/ml ; 0.00586 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

Yes
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

Yes
Log Kp (skin permeation)?

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

-6.15 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

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

1.0 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)

1.4

Application In Synthesis of [ 1591-37-3 ]

* 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.

  • Upstream synthesis route of [ 1591-37-3 ]
  • Downstream synthetic route of [ 1591-37-3 ]

[ 1591-37-3 ] Synthesis Path-Upstream   1~6

  • 1
  • [ 77326-36-4 ]
  • [ 124-41-4 ]
  • [ 1591-37-3 ]
YieldReaction ConditionsOperation in experiment
83% With methanol In N,N-dimethyl-formamide at 20℃; for 18 h; Inert atmosphere NaOMe(25percentwtinMeOH,325μL,1.42mmol,1.1eq.)wasaddedtoasolutionof2-amino-6-fluorobenzonitrile (176 mg, 1.29 mmol, 1.0 eq.) in DMF (1.00 mL) at roomtemperature, and stirred for 18 hours. The solution was concentrated in vacuo and theresidue stirred with H2O (10 mL) to give a beige precipitate. This was filtered underreducedpressure,theresiduedissolvedinEtOAcandconcentratedinvacuo,tituratedwithhexanes before remaining solvent was removed in vacuo giving 2-amino-6-methoxybenzonitrile(158mg,1.07mmol,83percent)asabeigeamorphoussolid;mp143–145°C,lit.136–140°C.13
63% at 20℃; for 9 h; Heating / reflux Example 2: Methyl- (2-cyano-3-methoxy-phenyl) sulfonamide; 2.1 : 2-Amino-6-methoxy-benzonitrile A solution of 70 g (0.5 mol) of 2-amino-6-fluoro-benzonitrile (prepared, e. g. according to US 4,504, 660) in 250 ml of N, N-dimethylformamide was initially charged and a solu- tion of 30.6 g (0.55 mol) sodium methoxide in 70 ml of methanol was added dropwise at room temperature while stirring. The mixture was then refluxed for 5 hours under stirring. The completion of the reaction was monitored by TLC. Additional 25 g of so- dium methoxide in 35 ml methanol were added and the reaction mixture was refluxed for additional 4 hours while stirring. The reaction mixture was concentrated under re- duced pressure, the resulting residue was triturated with water, sucked off and the ob- tained solids were dissolved in ethyl acetate. The resulting solution was concentrated in vacuo. The obtained residue was triturated with petroleum ether and sucked off to afford 48 g (63percent of theory) of a brownish solid having a melting point of 143-146°C.
63% at 20℃; for 9 h; Heating / reflux Example 2;: N,N-Dimethyl-2-cyano-3-methoxyphenylsulfonamide (Compound No. 2); 2.1 : 2-Amino-6-methoxybenzonitrile; EPO <DP n="33"/>A solution of 70 g (0.5 mol) of 2-amino-6-fluorobenzonitrile (prepared, e.g. according to US 4,504,660) in 250 ml of N,N-dimethylformamide was prepared, and a solution of 30.6 g (0.55 mol) of sodium methoxide in 70 ml of methanol was added dropwise at room temperature while stirring. The mixture was then refluxed for 5 hours with stirring. The completion of the reaction was monitored by TLC. An additional 25 g of sodium methoxide in 35 ml methanol were added and the reaction mixture was refluxed for an additional 4 hours while stirring. The reaction mixture was concentrated under reduced pressure. The resulting residue was triturated with water, filtered off with suction and the solids obtained were dissolved in ethyl acetate. The resulting solution was concen- trated in vacuo. The obtained residue was triturated with petroleum ether and filtered off with suction. Yield: 48 g (63percent of theory) of a brownish solid having a melting point of 143-146°C.
References: [1] Synthesis (Germany), 2017, vol. 49, # 1, p. 135 - 144.
[2] Patent: WO2005/35486, 2005, A1, . Location in patent: Page/Page column 49.
[3] Patent: WO2006/56433, 2006, A2, . Location in patent: Page/Page column 31-32.
  • 2
  • [ 38469-85-1 ]
  • [ 1591-37-3 ]
References: [1] Journal of Medicinal Chemistry, 1981, vol. 24, # 6, p. 742 - 748.
[2] Journal of Medicinal Chemistry, 1990, vol. 33, # 1, p. 434 - 444.
[3] Journal of Medicinal Chemistry, 2008, vol. 51, # 3, p. 449 - 469.
[4] Journal of Organic Chemistry, 1952, vol. 17, p. 149,153.
[5] Yakugaku Zasshi, 1955, vol. 75, p. 755[6] Chem.Abstr., 1955, p. 13939.
[7] Justus Liebigs Annalen der Chemie, 1912, vol. 388, p. 34.
[8] Journal of the American Chemical Society, 1977, vol. 99, p. 3734 - 3744.
[9] Patent: US4518597, 1985, A, .
  • 3
  • [ 67-56-1 ]
  • [ 77326-36-4 ]
  • [ 1591-37-3 ]
References: [1] Organic Letters, 2017, vol. 19, # 16, p. 4203 - 4206.
  • 4
  • [ 38469-85-1 ]
  • [ 1591-37-3 ]
References: [1] Patent: US4404230, 1983, A, .
  • 5
  • [ 35213-00-4 ]
  • [ 1591-37-3 ]
References: [1] Journal of Medicinal Chemistry, 1990, vol. 33, # 1, p. 434 - 444.
  • 6
  • [ 606-21-3 ]
  • [ 1591-37-3 ]
References: [1] Journal of Medicinal Chemistry, 1990, vol. 33, # 1, p. 434 - 444.
 

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