Structure of Cinacalcet Impurity 23
CAS No.: 454-89-7
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
Synonyms: 3-(Trifluoromethyl)benzaldehyde
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Selective and Cell-Active PBRM1 Bromodomain Inhibitors Discovered through NMR Fragment Screening
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.
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CAS No. : | 454-89-7 |
Formula : | C8H5F3O |
M.W : | 174.12 |
SMILES Code : | C1=C(C=CC=C1C(F)(F)F)C=O |
Synonyms : |
3-(Trifluoromethyl)benzaldehyde
|
MDL No. : | MFCD00003373 |
InChI Key : | NMTUHPSKJJYGML-UHFFFAOYSA-N |
Pubchem ID : | 67990 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 12 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.12 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 36.83 |
TPSA ? Topological Polar Surface Area: Calculated from |
17.07 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.58 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.47 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.67 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.52 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.98 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.64 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.71 |
Solubility | 0.337 mg/ml ; 0.00193 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.47 |
Solubility | 0.586 mg/ml ; 0.00337 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.23 |
Solubility | 0.103 mg/ml ; 0.000592 mol/l |
Class? Solubility class: Log S scale |
Soluble |
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) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-5.61 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
2.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.08 |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 269 4-Methoxy-3-(3-trifluoromethyl-benzylamino)-N-phenyl-benzamide The title compound has been made using the procedure of Example 50, but using 3-amino-4-methoxy-N-phenyl benzamide and 3-trifluoromethylbenzaldehyde as starting materials, which can be purchased from Aldrich; m.p. 167-171 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With sodium hydrogensulfite; In N,N-dimethyl acetamide; at 150℃; | General procedure: Sodium hydrogen sulfite (4 mmol) was added to a solution of anthranilamide 1 (2 mmol) and benzaldehyde 2 (2 mmol) in N,N- dimethylacetamide (5 mL). The mixture was heated under continuous stirring at 150 o C for 2-3 h and poured into ice water. The precipitate was then filtered, washed with water followed byethanol, and dried to yield the 2-arylquinazolinones 3-31.#10;#10; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With sodium methylate; In methanol; at 60℃; | Using the method of synthesizing an intermediate similar to that of Example 1,Take 0.01 mol of <strong>[13338-63-1]3,4,5-trimethoxyphenylacetonitrile</strong> (5), 0.01 mol of 3-trifluoromethylbenzaldehyde and 20 mL of methanol into a 50 mL three-necked flask.Stirring to 60 C, adding 0.005 mol of sodium methoxide, constant temperature reaction 4-6 h,TLC scanning and detection, after the reaction is completed, it is cooled to room temperature, filtered, washed with water, dried, and recrystallized from methanol to obtain a pale yellow solid. Yield: 43.0%, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | General procedure: The aldehyde (0.8 equivalent) and amine (0.7 equivalent) were dissolved in methanol (2.0 mL) and stirred for two to 3 h depending upon the starting material. The acid (100 mg, 1 equivalent) and isocyanide (0.7 equivalent) were added in the reaction mixture and further stirred. The reaction mixture was monitored using TLC analysis.Water (4 mL) was added upon completion of the reaction.The resulted solid was filtered off and dissolved in ethyl acetate(10 mL), washed with water (2 3 mL) and dried over sodium sulphate. The crude product was purified using silica gel column chromatography. The ethyl acetate:hexane (6:4) solvent system was used for the purification of these compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35.5% | General procedure: The aldehyde (0.8 equivalent) and amine (0.7 equivalent) were dissolved in methanol (2.0 mL) and stirred for two to 3 h depending upon the starting material. The acid (100 mg, 1 equivalent) and isocyanide (0.7 equivalent) were added in the reaction mixture and further stirred. The reaction mixture was monitored using TLC analysis.Water (4 mL) was added upon completion of the reaction.The resulted solid was filtered off and dissolved in ethyl acetate(10 mL), washed with water (2 3 mL) and dried over sodium sulphate. The crude product was purified using silica gel column chromatography. The ethyl acetate:hexane (6:4) solvent system was used for the purification of these compounds. |
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