Structure of 89031-84-5
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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.
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Tian, Gui-Long ; Hsieh, Chia-Ju ; Taylor, Michelle ; Lee, Ji Youn ; Riad, Aladdin A. ; Luedtke, Robert R. , et al.
Abstract: The difference in the secondary binding site (SBS) between the dopamine 2 receptor (D2R) and dopamine 3 receptor (D3R) has been used in the design of compounds displaying selectivity for the D3R versus D2R. In the current study, a series of bitopic ligands based on Fallypride were prepared with various secondary binding fragments (SBFs) as a means of improving the selectivity of this benzamide analog for D3R versus D2R. We observed that compounds having a small alkyl group with a heteroatom led to an improvement in D3R versus D2R selectivity. Increasing the steric bulk in the SBF increase the distance between the pyrrolidine N and Asp110, thereby reducing D3R affinity. The best-in-series compound was (2S,4R)-trans-27 which had a modest selectivity for D3R versus D2R and a high potency in the β-arrestin competition assay which provides a measure of the ability of the compound to compete with endogenous dopamine for binding to the D3R. The results of this study identified factors one should consider when designing bitopic ligands based on Fallypride displaying an improved affinity for D3R versus D2R.
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Keywords: Dopamine 2 receptor ; Dopamine 3 receptor ; Fallypride ; Bitopic ligands ; PET imaging
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Purchased from AmBeed: 89031-84-5 ; 40216-83-9 ; 88-13-1 ; 135042-17-0 ; 110-52-1 ; 488-93-7 ; 18742-02-4 ; 98-98-6 ; 86864-60-0 ; 62-23-7 ; 29886-64-4 ; 59741-04-7 ; 4385-62-0 ; 15268-31-2 ; 134441-72-8 ; 54751-01-8 ; 166173-78-0 ; 213131-32-9 ; 98-98-6 ; 69966-55-8 ; 154342-67-3
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CAS No. : | 89031-84-5 |
Formula : | C9H21BrOSi |
M.W : | 253.25 |
SMILES Code : | C[Si](C(C)(C)C)(OCCCBr)C |
MDL No. : | MFCD00216589 |
InChI Key : | QGMROEZDWJTIDW-UHFFFAOYSA-N |
Pubchem ID : | 607486 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H227-H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 12 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 1.0 |
Num. rotatable bonds | 5 |
Num. H-bond acceptors | 1.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 62.2 |
TPSA ? Topological Polar Surface Area: Calculated from |
9.23 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
3.36 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
3.98 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.79 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.99 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.64 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
3.15 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.59 |
Solubility | 0.0655 mg/ml ; 0.000258 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.88 |
Solubility | 0.0338 mg/ml ; 0.000133 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.78 |
Solubility | 0.042 mg/ml ; 0.000166 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 |
-5.02 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 |
1.0 |
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 |
2.0 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) |
4.64 |
* 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 |
---|---|---|
With sodium carbonate; In N,N-dimethyl-formamide; at 60℃; | To a suspension of ethyl 5-oxo-2,5-dihydro-1 H-pyrazole-3-carboxylate (5.47 g, prepared with an analogous procedure to that described in Preparation 1 ) and Na2CO3 (4.46 g) in dry DMF (36 ml_), [(3-bromopropyl)oxy](1 ,1-dimethylethyl)dimethylsilane (8.52 ml.) was added drop wise and the mixture was stirred at 6O0C overnight. [(3-bromopropyl)oxy](1 ,1- dimethylethyl)dimethylsilane (0.8 mL) was added and the mixture was stirred for additional 4h. After cooling, the mixture was diluted with AcOEt, washed with chilly water and brine, dried, filtered and evaporated under reduced pressure. The crude was purified by flash chromatography on silica column eluting with Cy/AcOEt with a gradient of Cy from 100% to 80% to give the title compound as yellow oil (5.63 g).1H NMR (CDCI3) delta: 10.53 (s, 1 H); 6.23 (s, 1 H); 4.38 (q, 2H); 4.27 (t, 2H); 3.79 (t, 2H); 2.0(m, 2H); 1.39 (t, 3H); 0.9 (s, 9H); 0.05 (s, 6H).MS (m/z): 328 [MH]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
612 mg | With caesium carbonate; In N,N-dimethyl-formamide; at 50℃; for 1.5h; | 1-(3-[tert-butyl(dimethyl)silyl]oxy}propyl)-3 FontWeight="Bold" FontSize="10" 3-difluoropiperidine To a solution of <strong>[496807-97-7]3,3-difluoropiperidine hydrochloride</strong> (518 mg) in DMF (15 mL) was added cesium carbonate (3.21 g) and (3-bromopropoxy)-tert-butyldimethylsilane (0.838 mL). The resulting reaction mixture was heated to 50C for 1.5 hours before cooling back to room temperature. Water and ethyl acetate were added to the reaction mixture. The mixture was extracted with ethyl acetate (2x). The combined organics were washed with water (2x), brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography (ISCO, 0 to 40% ethyl acetate in hexanes with 1% triethylamine) gave the desired product (612 mg). NMR (400 MHz, CDC13): delta (ppm) 4.20 (t, 1H), 3.71-3.64 (m, 2H), 3.46 (t, 1H), 2.62 (t, 1H), 2.50-2.47 (m, 1H), 2.44-2.42 (m, 1H), 2.05-1.98 (m, 1H), 1.91-1.82 (m, 2H), 1.77-1.67 (m, 4H), 0.89 (d, 9H), 0.05 (s, 3H), 0.04 (s, 3H). |
612 mg | With caesium carbonate; In N,N-dimethyl-formamide; at 50℃; for 1.5h; | To a solution of <strong>[496807-97-7]3,3-difluoropiperidine hydrochloride</strong> (518 mg) in DMF (15 mL) was added cesium carbonate (3.21 g) and (3-bromopropoxy)-tert-butyldimethylsilane (0.838 mL). The resulting reaction mixture was heated to 50 C. for 1.5 hours before cooling back to room temperature. Water and ethyl acetate were added to the reaction mixture. The mixture was extracted with ethyl acetate (2×). The combined organics were washed with water (2×), brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography (ISCO, 0 to 40% ethyl acetate in hexanes with 1% triethylamine) gave the desired product (612 mg). 1H NMR (400 MHz, CDCl3): delta (ppm) 4.20 (t, 1H), 3.71-3.64 (m, 2H), 3.46 (t, 1H), 2.62 (t, 1H), 2.50-2.47 (m, 1H), 2.44-2.42 (m, 1H), 2.05-1.98 (m, 1H), 1.91-1.82 (m, 2H), 1.77-1.67 (m, 4H), 0.89 (d, 9H), 0.05 (s, 3H), 0.04 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1 g | To a solution of crude 2-(dibenzylamino) ethanol (2.0 g) in DMF (30 mL) was added NaH (purity: 95%, 0.42 g, 16.6 mmol) portionwise at 0 C. The mixture was stirred for 30 minutes, then to the mixture was added 3-bromopropoxy-tert-butyl-dimethyl-silane (3.2 g, 12.5 mmol). The mixture was warmed to 60 C. and stirred at this temperature for 12 hours. After the reaction mixture was cooled to room temperature, the reaction was quenched with saturated aqueous ammonium chloride solution. The resulting mixture was extracted with DCM. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography to give N, N-dibenzyl-2-[3-[tert-butyl (dimethyl) silyl]oxypropoxy]ethanamine (1.0 g). | |
1 g | Step 2: Preparation of N, Lambda-dibenzy 1-2- 13- 1 fc'/Y-buty I (dimethyl)silylj oxypropoxy] ethanamine To a solution of crude 2-(dibenzylamino ) ethanol ( 2.0 g) in DMF (30 niL) was added Nai l (purity: 95%, 0.42 g. 16.6 mmol) portionwise at 0 C. The mixture was st irred for 30 minutes, then to the mixture was added 3-bromopropoxy-feri-butyi-dimethyl-silane (3.2 g, 12.5 mmol). The mixture was warmed to 60 C and st irred at this temperature for 12 hours. After the reaction mixture was cooled to room temperature, the reaction was quenched with saturated aqueous ammonium chloride solution. The resulting mixture was extracted with DCM. The organic layer was dried over anhydrous Na2S04 and concentrated. The residue was purified by column chromatography to give N, Lambda - d i be n zy 1 - 2 - [ 3 - [ r rt-b u t y 1 (dimethyl ) silyl j oxypropoxy] ethanaminc (1.0 g). |