2-(3,5-Dichlorophenyl)-6-benzoxazole carboxylic acid

Absorption

Tafamidis reaches a Cmax of 1430.93ng/mL with a Tmax of 1.75h fasted and 4h fed. The AUC of tafamidis is 47,864.31ng*h/mL.

Toxicity

Data regarding overdoses of tafamidis are not readily available. In a clinical trial, some patients were given up to 6 times the normal dose with one reported case of mild hordeolum.

Description

Tafamidis is a kinetic stabilizer of transthyretin (TTR) that prevents amyloidogenesis by wild-type and mutant TTRs. It binds to TTR with negative cooperativity (K_d1 = 3 nM; K_d2 = 278 nM) to stabilize the TTR dimer-dimer interface and inhibit tetrameric dissociation. Tafamidis stabilizes wild-type and clinically significant V30M and V122I mutant TTR amyloidogenic homotetramers (EC₅₀s = 2.7-3.2 μM) under fibril-promoting, denaturing, and physiological conditions in vitro. It stabilizes TTR heterotetramers containing wild-type and mutant subunits ex vivo in human plasma derived from patients carrying V30M or V1221 mutations when used at a concentration of 7.2 μM. Formulations containing tafamidis have been used for the treatment of familial amyloid polyneuropathy.

Description

Tafamidis, a molecule first described by J. W. Kelly and co-workers in 2003,?stabilizes the tetrameric protein transthyretin. When unstabilized transthyretin dissociates, misfolds, or aggregates, it causes amyloid deposition and can lead to the fatal diseases senile systemic amyloidosis, familial amyloid cardiomyopathy, and familial amyloid polyneuropathy. Tafamidis is well into Phase II and III clinical trials for treating these diseases.

The Uses of 2-(3,5-Dichlorophenyl)-6-benzoxazole carboxylic acid

Tafamidis can be used as a benzoxole derivative that is a transthyretin (TTR) amyloid fibril inhibitors. It is a new drug candidate in the treatment of TTR amyloidosis (caused my misfolding of proteins).

Background

Tafamidis and tafamidis meglumine (FX-1006A) are benzoxazole derivatives developed by FoldRX. Tafamidis is structurally similar to diflusinal.
Tafamidis was granted an EMA market authorisation on 16 November 2011 and FDA approval on 3 May 2019.

Indications

Tafamidis is indicated to treat cardiomyopathy of wild type or hereditary transthyretin-mediated amyloidosis in adults.

Definition

ChEBI: A member of the class of 1,3-benzoxazoles that is 1,3-benzoxazole-6-carboxylic acid in which the hydrogen at position 2 is replaced by a 3,5-dichlorophenyl group. Used (as its meglumine salt) for the amelioration of transthyretin-related hereditary amyloid sis.

Pharmacokinetics

Tafamidis stabilizes transthyretin tetramers, reducing the amount of monomers available for amyloidogenesis. It has a long duration of action as it is given once daily, and a wide therapeutic window.

Synthesis

The synthesis of 2-(3,5-Dichlorophenyl)-6-benzoxazole carboxylic acid is as follows:
methyl 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylate (17.9 mmol) was dissolved in a mixture of THF:MeOH:H2O (3:1:1, 50 mL) and treated with LiOH (71.6 mmol) at room temperature for 6h. The mixture was acidified to pH 2 with 1 N HCl and extracted with EA. The combined organic layers were dried over MgSO4, filtered and concentrated to give the product as a white solid 5.0 g, yield 91%.

Metabolism

Tafamidis is largely not subject to first pass or oxidative metabolism, being 90% unchanged after in in vitro experiments. Preclinical data suggest tafamidis is mainly metabolized through glucuronidation and excreted in bile.

References

1) Bulawa?et al.?(2012),?Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits amyloid cascade; Proc. Natl. Acad. Sci. USA,?109?9629 2) Scott (2014),?Tafamidis: a review of its use in familial amyloid polyneuropathy; Drugs,?74?1371 3) Zhao?et al.?(2019),?Tafamidis, a Noninvasive Therapy for Delaying Transthyretin Familial Amyloid Polyneuropathy: Systemic Review and Meta-analysis; J. Clin. Neurol.,?15?108 4) Lorenzini and Elliott (2019),?Tafamidis for the treatment of transthyretin amyloidosis; Future Cardiol.,?15?53