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 (EC
50s = 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
