Structure of 582-33-2
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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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Ganga Reddy Velma ; Megan S. Laham ; Cutler Lewandowski ; Ana C. Valencia-Olvera ; Deebika Balu ; Annabelle Moore , et al.
Abstract: Therapeutics enhancing apolipoprotein (APOE) positive function are a priority, because APOE4 is the major genetic risk factor for Alzheimer’s disease (AD). The function of APOE, the key constituent of lipoprotein particles that transport cholesterol and lipids in the brain, is dependent on lipidation by ABCA1, a cell_x005f_x0002_membrane cholesterol transporter. ABCA1 transcription is regulated by liver X receptors (LXR): agonists have been shown to increase ABCA1, often accompanied by unwanted lipogenesis and elevated triglycerides (TG). Therefore, nonlipogenic ABCA1-inducers (NLAI) are needed. Two rounds of optimization of an HTS hit, derived from a phenotypic screen, gave lead compound 39 that was validated and tested in E3/4FAD mice that express human APOE3/4 and five mutant APP and PSEN1 human transgenes. Treatment with 39 increased ABCA1 expression, enhanced APOE lipidation, and reversed multiple AD phenotypes, without increasing TG. This NLAI/LXR-agonist study is the first in a human APOE-expressing model with hallmark amyloid-β pathology.
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CAS No. : | 582-33-2 |
Formula : | C9H11NO2 |
M.W : | 165.19 |
SMILES Code : | CCOC(=O)C1=CC(N)=CC=C1 |
MDL No. : | MFCD00007794 |
InChI Key : | ZMCBYSBVJIMENC-UHFFFAOYSA-N |
Pubchem ID : | 11400 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 12 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.22 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 46.93 |
TPSA ? Topological Polar Surface Area: Calculated from |
52.32 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.87 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.14 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.45 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.64 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.31 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.68 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.38 |
Solubility | 0.682 mg/ml ; 0.00413 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.87 |
Solubility | 0.223 mg/ml ; 0.00135 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.51 |
Solubility | 0.509 mg/ml ; 0.00308 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 |
-5.79 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 |
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) |
1.34 |
* 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 |
---|---|---|
90.5% | With acetic acid; In ethanol; dichloromethane; | Step 3 Synthesis of N-isopropyl-alpha-[2-N-(1,1-dimethylethoxycarbonyl)aminothiazol-4-yl] nitrone (24) 2.22 9 (9.72 mmol) of compound 22, 3.47g (33.65 mmol) of 2-nitropropane (4), and 2.54 g (38.84 mmol) of zinc were placed in a round-bottomed flask along with 95% ethanol (50 mL) and cooled to 0 C. 4.67 g (77.77 mmol) of acetic acid was added slowly with stirring. The solution was allowed to come to room temperature, stirred for 6 hours. CH2Cl2 was added to the reaction mixture and it was filtered through a Celite pad and concentrated under reduced pressure. The residue was purified by short flash column chromatography (silica, Hex:EtOAc=1:1) to give 2.51 g (8.80 mmol) of compound 24 in 90.5% yield. 1H NMR (CDCl3): 8.71 (s, 1H), 7.63 (S, 1H), 4.21 (septet, J=6.6 Hz, 1H), 1.55 (s, 9H), 1.49 (d, J=6.6 Hz, 6H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Dissolved 0.500 g <strong>[17823-69-7]2-cyano-3,3-bis(methylthio)acrylamide</strong> in 15 mL EtOH and added Ethyl 3-aminobenzoate (1.0 eq.) . Stirred reaction at 75 C until starting amide was absent by HPLC. Once complete (18 hrs), reaction was brought to room temperature and filtered to obtain a light yellow powder as product. Product was allowed to dry under vacuum for 1 hr. Product was then suspended in 10 mL EtOH and hydrazine hydrate (1 eq.) was added dropwise. Reaction was heated at 75 C until intermediate was absent (HPLC). Once intermediate was absent (18 hrs), reaction was brought to room temperature and filtered to obtain ethyl 3-((5-amino-4-carbamoyl-lH-pyrazol-3-yl)amino)benzoate as a yellow powder. Product was allowed to dry under vacuum for 1 hr. ethyl 3-((5-amino-4-carbamoyl- lH-pyrazol-3-yl)amino)benzoate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In 1,4-dioxane; ethyl acetate; at 20℃; for 2h; | A mixture of ethyl 3-aminobenzoate (300 mg, 1.82 mmol) and 2-(5-fluoro-2-methoxy- phenyl)acetic acid (334 mg, 1.82 mmol) in 1,4-dioxane (5 mL) was treated with 50% T3P solution in EtOAc (2.31 mL, 1.82 mmol) and TEA (634 muL, 3.63 mmol). After stirring at room temperature for 2 hours, the mixture was partitioned between water (20 mL) and EtOAc (20 mL). The organic layer was separated, dried over Na2SO4 and concentrated in vacuo. Purification of the crude residue by chromatography on silica eluting with EtOAc in heptane afforded the titled compound as a white solid.1H NMR (500 MHz, DMSO-d6) delta 10.31 (s, 1H), 8.26 (t, J = 1.8 Hz, 1H), 7.86- 7.82 (m, 1H , 7.63 dt, J = 7.79, 1.2 Hz, 1H , 7.45 t, J = 7.9 Hz, 1H), 7.11 (dd, J = 9.2, 3.1 Hz, 1H),Hz, 1H), 4.31 (q, J = 7.1 Hz, 2H), 3.75 [M+H]+ (100% 215nm) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | To a solution of m-amino benzoic acid ethyl ester (1.65 g, 10.0 mmol) in concentrated HCl (10 mL) was added an aqueous solution (2.5 mL) of NaNO2 (690 mg, 1.0.0 mmol) at 0 C. the reaction mixture was stirred for 1 h. A solution of SnCl2.2H2O (4.52 g, 20 mmol) in concentrated HCl (1 mL) was then added at 0 C. The reaction solution was stirred for 2 h at room temperature. The precipitate was filtered and washed with ethanol and ether to yield ethyl 3-hydrazinobenzoate hydrogen chloride (2.1 g, yield 100%) as a white solid, which was used for the next reaction without further purification. 1H NMR (400 MHz, DMSO-d6): δ 9.09 (s, 1H), 7.68 (dd, J = 13.9, 8.2 Hz, 2H), 7.27 (d, J = 31.6 Hz, 2H), 4.97 (s, 3H), 3.92 (d, J = 5.5 Hz, 1H), 3.35 (s, 5H), 2.36 (s, 3H), 1.23 (s, 3H) ppm. MS: (M+H)+: m/z = 181.1. | |
100% | To a solution of m-amino benzoic acid ethyl ester (1.65 g, 10.0 mmol) in concentrated HCl (10 mL) was added an aqueous solution (2.5 mL) of NaNO2 (690 mg, 1.0.0 mmol) at 0 C. the reaction mixture was stirred for 1 h. A solution of SnCl2.2H2O (4.52 g, 20 mmol) in concentrated HCl (1 mL) was then added at 0 C. The reaction solution was stirred for 2 h at room temperature. The precipitate was filtered and washed with ethanol and ether to yield ethyl 3-hydrazinobenzoate hydrogen chloride (2.1 g, yield 100%) as a white solid, which was used for the next reaction without further purification. 1H NMR (400 MHz, DMSO-d6): δ 9.09 (s, 1H), 7.68 (dd, J = 13.9, 8.2 Hz, 2H), 7.27 (d, J = 31.6 Hz, 2H), 4.97 (s, 3H), 3.92 (d, J = 5.5 Hz, 1H), 3.35 (s, 5H), 2.36 (s, 3H), 1.23 (s, 3H) ppm. MS: (M+H)+: m/z = 181.1. |