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.
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With 4-methyl-morpholine; In 1-methyl-pyrrolidin-2-one; at 120℃;Sealed tube;
A mixture of 6-bromo-2-fluoro-3-methoxy-pyridine (2.030 mmo 1; 418.1 mg), tert-butyl N-[(3S)-3-piperidyl]carbamate (3.044 mmol; 609.7 mg), and N-Methylmorpholine (6.089 mmol;622 mg; 0.676 mL) in 1-methyl-2-pyrrolidinone (5 mL) in a sealed pressure vial was heated at120 C overnight. The mixture was poured into water, and extracted with EtOAc. The organiclayer was concentrated. The residue was purified on silica eluted with 0 to 40% EtOAc in Heptane to afford tert-butyl N-[(3S)-1-(6-bromo-3-methoxy-2-pyridyl)-3-piperidyl]carbamate(743.5 mg, 95%).
(S)-3-tert-butoxycarbonylamino-1,1-bis-[3-(3-methoxy-phenyl)-propyl]-piperidinium hydroxide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example 10.10 Intermediate 10.1.9: (S)-3-tert-Butoxycarbonylamino-1,1-bis-[3-(3-methoxy-phenyl)-propyl]-piperidinium hydroxide (S)-Piperidin-3-yl-carbamic acid tert-butyl ester (2.72 g, 13.6 mmol) and 1-(3-Bromo-propyl)-3-methoxy-benzene (6.6 g, 28.8 mmol), potassium carbonate (2.5 g, 18 mmol) and sodium iodide (4 g, 26.7 mmol) are dissolved in acetonitril (40 ml) and stirred at reflux for 1 day and the solvent is removed under vacuo. The residue is taken up in dichloromethane, filtered through a pad of silica, washed with a mixture of dichloromethane: methanol:conc.ammonia=4:1:0.1 and the filtrate is evaporated. LC (method L): tR=1.30 min; Mass spectrum (ESI+): m/z=497 [M]+.
With potassium carbonate; sodium iodide; In acetonitrile; for 24h;Reflux;
Example 10.10: Intermediate 10.1.9: (S)-3 -tert-Butoxycarbonylamino- 1 , 1 -bis- [3 -(3 -methoxy-phenyl)-propyl] - piperidinium hydroxide Chiral (S)-Piperidin-3-yl-carbamic acid tert-butyl ester (2.72 g, 13.6 mmol) and l-(3-Bromo-propyl)-3-methoxy- benzene (6.6 g, 28.8 mmol), potassium carbonate (2.5 g, 18 mmol) and sodium iodide (4 g, 26.7 mmol) are dissolved in acetonitril (40 ml) and stirred at reflux for 1 day and the solvent is removed under vacuo. The residue is taken up in dichloromethane, filtered through a pad of silica, washed with a mixture of di- chloromethane:methanol: cone. ammonia = 4: 1 :0.1 and the filtrate is evaporated. LC (method L): tR = 1.30 min; Mass spectrum (ESI+): m/z = 497 [M]+.
With potassium carbonate; In tetrahydrofuran; for 16h;Reflux;
in the step c, potassium carbonate (base 3, 8.49 g, 0.062 mol) was replaced by potassium carbonate (base 3, 0.85 g, 0.006 mol), and (R)-3-tert-butoxycarbonylaminopiperidine (Compound IV, 8.21 g, 0.041 mol) was replaced by (S)-3-tert-butoxycarbonylaminopiperidine (Compound IV, 0.82 g, 0.004 mol), and the mixture was heated to reflux for 16 hours, cooled to room temperature, added with 30 mL of water, stirred and filtered, and the filter cake was dissolved in 50 mL of dichloromethane. (0185) Yield: 1.52 g (65% of theoretical value) (0186) MS: [M+H]+=573.4
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