| Identification | Back Directory | [Name]
BAF-312(SiponiMod) | [CAS]
1230487-00-9 | [Synonyms]
CS-1753
SiponiMod
Siponimod D11
Siponimod [INN]
BAF-312(SiponiMod)
Siponimod (BAF-312)
BAF-312(SiponiMod) USP/EP/BP
SIPONIMOD; SIPONIMOD [INN]; BAF-312; BAF 312
(E)-1-(4-(1-(4-cyclohexyl-3-(trifluoromethyl)benzyloxyimino)ethyl)-2-ethylbenzyl)azetidine-3-carboxylic acid
1-(4-[1-[(E)-4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino]-ethyl]-2-ethyl-benzyl)-azetidine-3-carboxylic acid
3-Azetidinecarboxylic acid, 1-[[4-[(1E)-1-[[[4-cyclohexyl-3-(trifluoromethyl)phenyl]methoxy]imino]ethyl]-2-ethylphenyl]methyl]-
BAF312 (Siponimod) 1-[[4-[(E)-N-[[4-cyclohexyl-3-(trifluoromethyl)phenyl]methoxy]-C-methylcarbonimidoyl]-2-ethylphenyl]methyl]azetidine-3-carboxylic acid | [Molecular Formula]
C29H35F3N2O3 | [MDL Number]
MFCD26142651 | [MOL File]
1230487-00-9.mol | [Molecular Weight]
516.59 |
| Chemical Properties | Back Directory | [Melting point ]
154 - 157°C | [Boiling point ]
602.0±65.0 °C(Predicted) | [density ]
1.24±0.1 g/cm3(Predicted) | [storage temp. ]
Hygroscopic, Refrigerator, under inert atmosphere | [solubility ]
DMSO (Slightly), Methanol (Slightly) | [form ]
Solid | [pka]
2.69±0.20(Predicted) | [color ]
White to Off-White | [InChIKey]
KIHYPELVXPAIDH-HNSNBQBZSA-N | [SMILES]
N1(CC2=CC=C(/C(=N/OCC3=CC=C(C4CCCCC4)C(C(F)(F)F)=C3)/C)C=C2CC)CC(C(O)=O)C1 |
| Hazard Information | Back Directory | [Description]
S1p signaling is important for immune, cardiovascular, and CNS function.Like its FDA
approved predecessor fingolimod, siponimod is an oral S1p signaling modulator.While fin-
golimod binds four out of five known S1p receptors, siponimod is selective for receptor sub-
types 1 and 5. This selectivity may allow for an improved adverse event profile. | [Uses]
Siponimod is a functional sphingosine -1 phosphate (SIP) antagonist used in the treatment of multiple sclerosis and other central nervous system-related diseases in human subjects. . | [Side effects]
Siponimod,2 mg/day, was studied in a Phase I placebo-controlled trial in patients with secondary progressive Ms.206The primary endpoint was time to 3 months confirmed dis- ability progression. There were substantive side effects from the drug，mainly increased liver transaminase concentrations,bradycardia, and bradyarrhythmia at treatment initiation.With subsequent siponimod administration，there was an increased incidence of macular edema, hypertension,varicella zoster reactivation, and convulsions compared to placebo. By grad- ually escalating the initial dose of siponimod, cardiac first-dose effects were reduced.While the results of this trial are encouraging,long- term safety issues may be a greater concern5or since persons with secondary progressive MS as a group are older,with a higher incidence of comorbidities that could preclude use of siponimod. | [Synthesis]
Synthesis of BAF-312(SiponiMod)
 | [in vivo]
Siponimod (1 g/kg; i.v.; single dose) shows low to moderate in monkey, but high in rat in metabolism studies with liver microsomes. The absolute bioavailability is 50 and 71% in the rat and monkey, respectively, indicating no major presystemic first pass metabolism[1].
Siponimod (0.3, 3 mg/kg; p.o.; once daily; 23 d) suppresses experimental autoimmune encephalomyelitis (EAE) in rats by internalizing S1P1 receptors[2].
Parmacokinetics of Siponimod in rats and monkey[1]
| /td>
| CL (L/h/kg) | Vss (L/kg) | T1/2 (h) | F (%) | | Rat | 0.36 | 2.15 | 6 | 50 | | Monkey | 0.098/td>
| 2.12 | 19 | 71 |
| Animal Model: | Experimental autoimmune encephalomyelitis (EAE) model in Lewis rats (200-250 g)[2] | | Dosage: | 0.03, 0.3, 3 mg/kg | | Administration: | Oral gavage; once daily; 23 days | | Result: | Decreased peripheral lymphocyte counts by 88% at the Tmax of 8 h postadministration.
|
| [target]
S1P1 receptors | [IC 50]
S1PR1: 0.39 nM (EC50); S1PR5: 0.98 nM (EC50); S1PR4: 750 nM (EC50); S1PR3: >1000 nM (EC50); S1PR2: >10000 nM (EC50) | [References]
[1] gergely p1, nuesslein-hildesheim b, guerini d, brinkmann v, traebert m, bruns c, pan s, gray ns, hinterding k, cooke ng, groenewegen a, vitaliti a, sing t, luttringer o, yang j, gardin a, wang n, crumb wj jr, saltzman m, rosenberg m, wallstr?m e. the selective sphingosine 1-phosphate receptor modulator baf312 redirects lymphocyte distribution and has species-specific effects on heart rate. br j pharmacol. 2012 nov;167(5):1035-47.
[2] pan s1, gray ns1, gao w1, mi y1, fan y1, wang x1, tuntland t1, che j1, lefebvre s1, chen y1, chu a1, hinterding k2, gardin a2, end p2, heining p2, bruns c2, cooke ng2, nuesslein-hildesheim b2 .discovery of baf312 (siponimod), a potent and selective s1p receptor modulator. acs med chem lett. 2013 jan 4;4(3):333-7. |
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| Company Name: |
LETOPHARM LIMITED
|
| Telephone: |
+86-21-5821 5861 |
| Website: |
www.letopharm.com |
|