| Identification | Back Directory | [Name]
5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole | [CAS]
1570496-34-2 | [Synonyms]
CS-2899
CPD1805
IACS-10759
IACS-010759 (IACS-10759 )
IACS-10759 (IACS-010759 )
IACS-010759; IACS 010759; IACS010759; IACS-10759; IACS 10759; IACS10759
5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-ox
5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole
5-[5-Methyl-1-[[3-(4-methylsulfonylpiperidin-1-yl)phenyl]methyl]-1,2,4-triazol-3-yl]-3-[4-(trifluoromethoxy)phenyl]-1,2,4-oxadiazole
Piperidine, 4-(methylsulfonyl)-1-[3-[[5-methyl-3-[3-[4-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl]-1H-1,2,4-triazol-1-yl]methyl]phenyl]-
4-(Methylsulfonyl)-1-[3-[[5-methyl-3-[3-[4-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl]-1H-1,2,4-triazol-1-yl]methyl]phenyl]piperidine (IACS-010759) | [Molecular Formula]
C25H25F3N6O4S | [MDL Number]
MFCD30489429 | [MOL File]
1570496-34-2.mol | [Molecular Weight]
562.56 |
| Chemical Properties | Back Directory | [Boiling point ]
768.0±70.0 °C(Predicted) | [density ]
1.48±0.1 g/cm3(Predicted) | [storage temp. ]
Store at -20°C | [solubility ]
DMSO:24.23(Max Conc. mg/mL);43.07(Max Conc. mM)
DMF:0.1(Max Conc. mg/mL);0.18(Max Conc. mM) | [form ]
A crystalline solid | [pka]
3.24±0.40(Predicted) | [color ]
White to off-white | [InChIKey]
HWJWNWZJUYCGKV-UHFFFAOYSA-N | [SMILES]
N1(C2=CC=CC(CN3C(C)=NC(C4ON=C(C5=CC=C(OC(F)(F)F)C=C5)N=4)=N3)=C2)CCC(S(C)(=O)=O)CC1 |
| Hazard Information | Back Directory | [Uses]
4-(Methylsulfonyl)-1-[3-[[5-methyl-3-[3-[4-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl]-1H-1,2,4-triazol-1-yl]methyl]phenyl]piperidine is a drug candidate that acts as a modulator of HIF activity for treatment of cancer and other hypoxia-mediated diseases. | [Synthesis]
2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (580 mg, 1.25 mmol) and tris(dibenzylideneacetone)dipalladium (760 mg, 0.83 mmol) were added to 5-(1-(3-bromobenzyl)-5-methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2 ,4-oxadiazole (2.00 g, 4.16 mmol), 4-methanesulfonylpiperidine (1.02 g, 6.24 mmol) and sodium tert-butanolate (800 mg, 8.33 mmol) in a solution of toluene (80 mL). The reaction mixture was degassed with argon for 3 minutes and then heated to 140 °C under argon atmosphere and kept for 18 hours. Upon completion of the reaction, the mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), filtered through a pad of diatomaceous earth and washed with ethyl acetate (100 mL). The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1 followed by pure ethyl acetate) to give the crude product. The crude product was treated with ethyl acetate and ether (1:9, 30 mL, v/v), and the resulting suspension was stirred at room temperature for 30 min and filtered to afford 5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1 ,2,4-triazol-3- yl)-3-(4-(trifluoromethoxy)phenyl)-1 ,2,4-oxadiazole as a white solid (905 mg, 39% yield). The product was characterized by 1H NMR, 13C NMR, 19F NMR and HRMS. | [in vivo]
IACS-010759 (5, 10, 25 mg/kg/day; oral; for 21 d) results in tumor regression with minimal body weight loss at the 5 or 10 mg/kg dose in mice bearing NB-1 (PGD-null) subcutaneous xenografts. IACS-010759 at the 25 mg/kg dose is not tolerated[1].
IACS-010759 HCl (10 mg/kg; orally; QD (daily) or QD×5 (5 d on/2 d off); for 35 d) increases median survival from 28 d to longer than 60 d, whereas less-frequent dosing schedules (Q2D or Q3D) enhances survival to a lesser extent[1].
IACS-010759 (0.3 mg/kg for iv; 1 mg/kg for oral) has low plasma clearance with a high volume of distribution, resulting in a prolonged terminal half-life (>24 h)[1].
| [References]
[1] Nature Medicine, 2018, vol. 24, # 7, p. 1036 - 1046
[2] Patent: WO2014/31936, 2014, A2. Location in patent: Paragraph 0355
[3] Patent: US2015/239876, 2015, A1. Location in patent: Paragraph 0236; 0240 |
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