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A-971432

MCE China：A-971432

Brand：MedChemExpress (MCE)

Cat. No.HY-110291

CAS：1240308-45-5

Purity：99.0%

Storage：Powder -20°C 3 years In solvent -80°C 6 months -20°C 1 month

Shipping：Room temperature in continental US; may vary elsewhere.

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 .

In Vitro：A-971432 (compound 29) (0-10 μM) shows selectivity with IC50s of 0.362, >10, 0.006 μM for S1P1, S1P3, S1P5 respectively[1]. A-971432 (0.1-1000 nM) induces full agonism with an EC50s of 5.7 nM and 4.1 nM for HEK cells and CHO cells, respectively[1].

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 86 Balb/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].

IC50 & Target：S1P5[1][2] Cellular Effect Cell Line Type Value Description References

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References：

[1]. 1、Hobson AD,et al. Discovery of A-971432, An Orally Bioavailable Selective Sphingosine-1-Phosphate Receptor 5 (S1P5) Agonist for the Potential Treatment of Neurodegenerative Disorders. J Med Chem. 2015 Dec 10;58(23):9154-70.  [Content Brief]

[2]. Di Pardo A, et al. Stimulation of S1PR5 with A-971432, a selective agonist, preserves blood-brain barrier integrity and exerts therapeutic effect in an animal model of Huntington's disease. Hum Mol Genet. 2018 Jul 15;27(14):2490-2501.  [Content Brief]