BAF-312(SiponiMod)

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

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, wallström 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.