Tafamidis

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.

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).

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.

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%.

[1] CHRISTINE E BULAWA. Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascade.[J]. Proceedings of the National Academy of Sciences of the United States of America, 2012: 9629-9634. DOI:10.1073/pnas.1121005109
[2] SCOTT L J. Tafamidis: a review of its use in familial amyloid polyneuropathy.[J]. Drugs, 2014, 74 12: 1371-1378. DOI:10.1007/s40265-014-0260-2
[3] YINAN ZHAO. Tafamidis, a Noninvasive Therapy for Delaying Transthyretin Familial Amyloid Polyneuropathy: Systematic Review and Meta-Analysis.[J]. Journal of Clinical Neurology, 2019, 15 1: 108-115. DOI:10.3988/jcn.2019.15.1.108
[4] MASSIMILIANO LORENZINI  Perry M E. Tafamidis for the treatment of transthyretin amyloidosis.[J]. Future cardiology, 2019, 15 2: 53-61. DOI:10.2217/fca-2018-0078