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VALILTRAMIPROSATE
VALILTRAMIPROSATE
1034190-08-3
- (S)-3-(2-Amino-3-methylbutanamido)propane-1-sulfonic acid
- BLU8499
- WHO 11912
| Molecular Weight | 238.30 |
|---|---|
| Formula | C8H18N2O4S |
| CAS No. | 1034190-08-3 |
ALZ-801
Synonyms: valiltramiprosate, NRM-8499, homotaurine prodrug, 3-APS
This is a prodrug of homotaurine, a modified amino acid previously developed under the names tramiprosate and Alzhemed™. ALZ-801 is converted to homotaurine in vivo, but is more easily absorbed and lasts longer in the blood than tramiprosate.
Tramiprosate was reported to inhibit Aβ42 aggregation into toxic oligomers (Gervais et al., 2007; Kocis et al., 2017). Both ALZ-801 and tramiprosate are metabolized to 3-sulfopranpanoic acid (3-SPA), which is normally found in brain and also inhibits Aβ42 aggregation (Hey et al., 2018). A more recent study found that homotaurine activates GABA receptors, and suggests an alternative mechanism of action for ALZ-801 (Meera et al., 2023).
After tramiprosate failed in Phase 3, its maker, NeuroChem, marketed it as a nutritional supplement. Years later, a subgroup analysis of the trial data indicated a potential positive effect in participants who carried two copies of ApoE4 (Abushakra et al., 2016; Abushakra et al., 2017). Alzheon licensed ALZ-801 from NeuroChem and is developing it for Alzheimer’s disease.
ALZ-801 is a potent and orally available small-molecule β-amyloid (Aβ) anti-oligomer and aggregation inhibitor, valine-conjugated proagent of Tramiprosate with substantially improved PK properties and gastrointestinal tolerability compared with the parent compound. ALZ-801 is an advanced and markedly improved candidate for the treatment of alzheimer’s disease.
SCHEME
REF 1
US20080146642
https://patents.google.com/patent/US20080146642A1/en
HCL WATER, Dowex™ Marathon™ C ion-exchange column
General/Typical Procedure: [0311] (i) The solid material was dissolved in water (25 mL). The solution was passed through a Dowex™ Marathon™ C ion-exchange column (strongly acidic, 110 g (5 eq), prewashed). The strong acidic fractions were combined and treated with concentrated HCl (10 mL). The mixture was stirred at 50° C. for 30 minutes, and then was concentrated to dryness. The residual material was co-evaporated with EtOH (ethanol) to completely remove water. EtOH (100 mL) was added to the residue. The mixture was stirred at reflux for 1 h, and then cooled to room temperature. The solid material was collected by filtration. The solid material was dissolved in water (10 mL). The solution was added drop wise to EtOH (100 mL). The product slowly crystallized. The suspension was stirred at room temperature for 30 minutes. The solid material was collected by filtration and it was dried in a vacuum oven (60° C.). ID A2. 1H NMR (D2O).δ. 0.87-0.90 (m, 6H), 1.83 (qt, J = 7.2 Hz, 2H), 2.02-2.09 (m, 1H), 2.79 (t, J = 7.8 Hz, 2H), 3.20-3.29 (m, 2H), 3.60 (d, J = 6.3 Hz, 2H); 13C NMR (D2O).δ. 17.20, 17.77, 24.11, 30.00, 38.29, 48.63, 58.96, 169.35; m/z 237 (M-1).
- [1]. John A. Hey, et al. Discovery and Identification of an Endogenous Metabolite of Tramiprosate and Its Prodrug ALZ-801 that Inhibits Beta Amyloid Oligomer Formation in the Human Brain. CNS Drugs. 2018; 32(9): 849–861.[2]. Hey JA, et al. Clinical Pharmacokinetics and Safety of ALZ-801, a Novel Prodrug of Tramiprosate in Development for the Treatment of Alzheimer’s Disease. Clin Pharmacokinet. 2018 Mar;57(3):315-333. [Content Brief]
////////VALILTRAMIPROSATE, ALZ-801, ALZ 801, BLU 8499, WHO 11912
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