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

Boiling point:

486.7±40.0 °C(Predicted)

Density 

1.530

storage temp. 

-20°

solubility 

Soluble in DMSO (up to 20 mg/ml).

pka

3.49±0.30(Predicted)

form 

solid

color 

Off-white

Stability:

Stable for 2 years from date of purchase as supplied. Solutions in DMSO may be stored at -20° for up to 3 months.

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

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.

Uses

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).

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.

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%.

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

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