Virtual screening of ZINC database
We used the anchor motif as template to design and refine pharmacophore
models to virtually screen more than 27 million compounds using the
public server ZINCPharmer (Koes & Camacho, 2012). Based on
A1R2 configuration we screened near to
27 million commercially available compounds using ZINCPharmer, resulting
in the compounds studied here.
Synthesis of CBD3063
Step 1. 3-acetamidopiperidine-1-carbonyl chloride
In a cooled (0 °C) solution of N -(piperidin-3-yl)acetamide (500
mg, 3.52 mmol) in anhydrous dichloromethane (20 mL) was added
NaHCO3 (1.10 g, 10.6 mmol) and triphosgene (696 mg, 2.34
mmol). The mixture was stirred at room temperature for 1 hour. After all
starting material has been consumed, the mixture was filtered, and the
collected filtrate was evaporated under reduced pressure. The resulting
residue was then allowed to passed through a short silica plug (wash
with 100% EtOAc) to yield crude 3-acetamidopiperidine-1-carbonyl
chloride (467 mg, 65%) as sticky transparent liquid (HRMS calcd for
C8H14ClN2O2+[M+H]+: 205.0748; found: 205.0738). The compound
was used immediately for the next step without further purification.
Step 2.
3-acetamido-N -(3-(pyridin-2-ylamino)propyl)piperidine-1-carboxamide
3-acetamidopiperidine-1-carbonyl chloride (100 mg, 0.489 mmol) from the
previous step was dissolved in anhydrous dichloromethane (5.0 mL). Into
this solution was added Na2CO3 (104 mg,
0.977 mmol) andN 1-(pyridin-2-yl)propane-1,3-diamine (73.9 mg,
0.489 mmol). The mixture was stirred for 2 hours, upon which all
starting material had reacted. The mixture was filtered, and the
collected filtrate was evaporated under reduced pressure. The resulting
residue was then purified by flash column chromatography (gradient
elution of 0% to 10% MeOH in CH2Cl2)
to yield3- acetamido-N -(3-(pyridin-2-ylamino)propyl)piperidine-1-carboxamide
(137 mg, 88%) as white foam solid. 1H NMR (600 MHz,
CDCl3) δ 7.99 (dd, J = 4.1, 0.8 Hz, 1H), 7.38
(ddd, J = 8.7, 7.1, 1.9 Hz, 1H), 6.53 (ddd, J = 7.0, 5.2,
0.8 Hz, 1H), 6.41 (d, J = 8.4 Hz, 1H), 6.12 (d, J = 6.5
Hz, 1H), 5.79 (t, J = 5.5 Hz, 1H), 5.10 – 4.95 (m, 1H), 3.99 –
3.86 (m, 1H), 3.45 – 3.36 (m, 6H), 3.32 (q, J = 6.1 Hz, 2H),
1.95 (s, 3H), 1.87 – 1.62 (m, 5H), 1.61 – 1.49 (m, 1H).13C NMR (151 MHz, CDCl3) δ 170.10,
158.60, 158.46, 147.02, 137.59, 112.50, 108.28, 48.66, 45.61, 44.60,
38.63, 37.69, 30.22, 29.40, 23.37, 22.23. HRMS calcd for
C16H25N5O2Na
[M+Na]+: 342.1900; found: 342.1908.