Selective androgen receptor degrader (SARD) ligands and methods of use thereof
An androgen receptor, selective technology, applied in and including the field of heterocycles, can solve the problem of non-existent improvement of disease treatment
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example 1
[0670] Synthesis of SARD
[0671] Synthesis of intermediates 9-10
[0672]
[0673] Scheme 1. Synthesis of intermediates 9-10.
[0674] (2R)-1-Methacryloylpyrrolidine-2-carboxylic acid (2)
[0675] D-Proline (1, 14.93 g, 0.13 mol) was dissolved in 71 mL of 2N NaOH and cooled in an ice bath. The resulting basic solution was diluted with acetone (71 mL). A solution of methacryloyl chloride (13.56 g, 0.13 mol) in acetone (71 mL) and 2N NaOH solution (71 mL) were added simultaneously to the aqueous solution of D-proline in an ice bath over 40 minutes. The temperature of the mixture was maintained at 10-11 °C during the addition of methacryloyl chloride. After stirring (3 hours (h), room temperature (RT)), the mixture was evaporated in vacuo at a temperature of 35-45 °C to remove acetone. The resulting solution was washed with ether and acidified to pH 2 with concentrated HCl. The acidic mixture was saturated with NaCl and extracted with EtOAc (100 mL x 3). The comb...
example 2
[0693] Androgen receptor binding, transactivation, degradation and metabolism of pyrazole, indole, benzotriazole and indazole SARDs
[0694] Ligand binding assay
[0695] Objective: To determine the binding affinity between SARD and AR-LBD.
[0696] Methods: The hAR-LBD(633-919) was cloned into pGex4t.1. Large-scale GST-tagged AR-LBD was prepared and purified using a GST column. Recombinant AR-LBD with [ 3 H] Mibolerone (PerkinElmer, Waltham, MA) was combined in buffer A (10 mM Tris, pH 7.4, 1.5 mM edetate disodium, 0.25 M sucrose, 10 mM sodium molybdate, 1 mM PMSF) to determine [ 3 H] The equilibrium dissociation constant (K d ). Proteins with and without high concentrations of unlabeled mibolone with increasing concentrations of [ 3 H] mibolerone were incubated together for 18 hours at 4°C in order to determine total and non-specific binding. Non-specific binding is then subtracted from total binding to determine specific binding and non-linear regression of the ligan...
example 3
[0731]
[0732] Synthesis of 3,5-difluoro-1H-indole
[0733] To a 50 mL round bottle flask with a magnetic stir bar add (872mg, 2.0mmol, 2.0eq), Li 2 CO 3 (296 mg, 4.0 mmol, 4.0 equiv), dichloromethane (3.3 mL) and water (1.7 mL). Carboxylic acid (1.0 mmol, 1.0 equiv) was then added. The reaction mixture was stirred in an ice bath for 2 hours. The reaction mixture was diluted with water (40 mL), then extracted with DCM (20 mL×2). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by flash column chromatography (n-Hexane:DCM=2:1) to give 3,5-difluoro-1H-indole as dark brown oil. Yield = 68%;
[0734] MS(ESI)m / z 154.83[M+H] + ;152.03[M-H] - ;
[0735] 1 H NMR (CDCl 3 ,400MHz)δ7.86(bs,1H,NH),7.25(dd,J=9.2,2.4Hz,1H),7.20-7.16(m,1H),6.97(t,J=2.6Hz,1H),6.93 (dd,J=9.2,2.4Hz,1H);
[0736] 19 F NMR (CDCl 3 )δ-123.99(d,J F-F =2.8Hz), -174.74(d, J F-F = 4.0Hz).
[073...
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