| Description |
A-971432 is a potent, selective and orally active sphingosine-1-phosphate (S1P) receptor 5 agonist with IC50s of .362, >10, 0.006 µM for S1P1, S1P3, S1P5 respectively. A-971432 protects blood–brain barrier (BBB) homeostasis. A-971432 reverses age-related cognitive decline. A-971432 has the potential for the research of alzheimer’s disease or multiple sclerosis [1][2].
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| In Vivo |
A-971432 (1, 2 mg/kg; p.o.) shows excellent PK characteristics and oral bioavailability[1]. A-971432 (0.1 mg/kg; P.o.; daily for 21 days) shows pro-cognitive impact in a dose-dependent manner[1]. A-971432 (11 weeks R6/2 mice; 0.1 mg/kg; i.p.) increases the phosphorylation of AKT and ERK and significantly incremented the levels of BDNF in the cortex[2]. A-971432 (0.1 mg/kg; i.p.) attenuates the classic progressive BBB leakage and therefore the FITC-albumin extravasation in striatal parenchyma, and protects blood–brain barrier (BBB) homeostasis and suppresses aggregation of mHtt in the CNS blood vessels[2]. A-971432 (0.1 mg/kg; i.p.; daily for 4 weeks) prevents the worsening of motor deficit in symptomatic R6/2 mice by chronic infusion[2]. Pharmacokinetic Parameters of A-971432 in Balb/C mice, SD rat, beagle dog, cyno monkey[1]. IV PO species dose (mg/kg) sample analyzed) protein binding (%) t1/2 (h) AUC (ng.h/mL) VL (L/h/kg) Vss(L/kg) t1/2 (h) tmax (h) Cmax (ng/mL) AUC (ng.h/mL) F(%) BALB/C mouse 2 plasma 93 7.6 8500 0.24 1.9 7.4 2.0 300 4800 57 BALB/C mouse 2 brain nd 9.8 3200 (Cmax=133 ng/nL) nd nd 10 2-24 43 1600 56 SD rat 1 plasm 93 9.0 6400 0.16 1.3 14 4.3 400 8700 >100 SD rat 2 brain 99.5 nd nd nd nd 15 8 120 3100 nd beagle dog 1 plasma 96 9.3 12000 0.09 1.2 10 1.5 690 11000 92 cyno monkey 1 plasma 97 3.5 6400 0.16 0.82 6.7 1.7 650 5500 86Balb/C mice, SD rat, beagle dog, cyno monkey; p.o. or i.v.; 2 mg/kg for Balb/C mice, SD rat; 1mg/kg for SD rat, beagle dog, cyno monkey[1]. Animal Model: Balb/C mice, SD rat, beagle dog, cyno monkey[1] Dosage: 1, 2 mg/kg Administration: P.o. or i.v. Result: Showed high oral bioavailability, high exposure, low clearance, a long half-life. Animal Model: Male C57BL6J mice[1] Dosage: 0.1 mg/kg Administration: P.o.; daily for 21 days Result: Showed pro-cognitive impact in a dose-dependent manner. Animal Model: 7-week R6/2 mice[2] Dosage: 0.1 mg/kg Administration: I.p.; daily for 4 weeks Result: Restored normal motor function within the first week of treatment, and preserved them from the gradual motor deficit, classically occurring during the disease, for the entire period of the treatment. Animal Model: 4-week R6/2 mice[2] Dosage: 0.1 mg/kg Administration: I.p., daily for 2 weeks Result: Preserved BBB integrity and delayed the onset of motor symptoms in R6/2 mice and suppressed aggregation of mHtt in the CNS blood vessels.
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