Uses
Odevixibat (A4250) is a selective and orally active ileal apical sodium-dependent bile acid transporter (ASBT) inhibitor. Odevixibat decreases cholestatic liver and bile duct injury in mice model. Odevixibat has the potential for the treatment of primary biliary cirrhosis[1].
Indications
Odevixibat is approved for the treatment of pruritus in patients with progressive familial intrahepatic cholestasis (PFIC) and has been granted orphan drug designation in the U.S. and EU for the treatment of Alagille syndrome, biliary atresia, and primary biliary cholangitis.
Biological Activity
Odevixib at is an orally active, potent and selective ileal bile acid transporter (IBAT; ASBT; SLC10A2) inhibitor th at improves cholestatic liver and bile duct injury in a mouse model of sclerosing cholangitis (0.01% w/w in diet).
Mechanism of action
PFIC is a rare, inherited hepatobiliary disorder characterized by impaired bile formation and/or flow in the liver, leading to accumulation of bile components in the liver, which in turn causes hepatitis, fibrosis, and liver damage. Odevixibat reduces plasma/serum bile acid levels by reducing bile acid absorption in the terminal ileum and increasing colonic clearance.
Synthesis
Odevixibat was synthesized by using 3-mercaptoether anisole as the starting material and reacting with the intermediate amine fragment 12.4. The specific reaction route is as follows:
3-Mercaptoether anisole 12.5 was dibrominated with bromine in methanol to produce dibromodisulfide 12.6, which was then oxidized to sulfonyl chloride 12.7 in a one-pot process. In an SN2 reaction, tertiary amine 12.4 reacted with arylsulfonyl chloride 12.7 to produce 12.8. This compound was treated with copper powder and K2CO3 in DMF to form 12.9. Under the protection of p-methoxybenzyl bromide, the sulfonamide nitrogen was first demethylated, and then the sulfide group was introduced by SNAr reaction to finally give phenol 12.10. The peptide side chain was then constructed and O-alkylated with tert-butyl bromoacetate, followed by removal of the protecting group under acidic conditions to give 12.11. Next, two consecutive amidation reactions were carried out using the activating agent TBTU. Amine 12.12 was coupled with 12.11, followed by removal of the tert-butyl group with trifluoroacetic acid (TFA). A second amidation reaction with amine 12.14, accompanied by in situ removal of the tert-butyl group, provided odevixibat (12) in 66% yield.
in vivo
Odevixibat (A4250)(0.01% (w/w) in chow diet; 4 weeks) improves sclerosing cholangitis and significantly reduces serum alanine aminotransferase, alkaline phosphatase and BAs levels, hepatic expression of pro-inflammatory and pro-fibrogenic genes and bile duct proliferation in Mdr2-/- mice[1].
In addition, Odevixibat (A4250) significantly reduces bile flow and biliary BA output, which correlates with reduced bsep transcription, while Ntcp and Cyp7a1 are induced[1].
| Animal Model: | Eight week old Mdr2-/- (Abcb4-/-) mice (model of cholestatic liver injury and sclerosing cholangitis)[1] |
| Dosage: | 0.01% (w/w) in chow diet |
| Administration: | 4 weeks |
| Result: | Decreased cholestatic liver and bile duct injury in mice model. |
References
[1] Baghdasaryan A, et al. Inhibition of intestinal bile acid absorption improves cholestatic liver and bile duct injury in a mouse model of sclerosing cholangitis.J Hepatol. 2016 Mar;64(3):674-81. DOI:
10.1016/j.jhep.2015.10.024
