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].
| 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. |
