Tafamidis Meglumine

Description

In November 2011, the European Commission approved tafamidis meglumine (Fx-1006A, PF-06291826) for the treatment of transthyretin familial amyloid polyneuropathy (TTR-FAP) in adult patients with stage 1 symptomatic polyneuropathy. Tafamidis stabilizes both the wild type and mutant forms of TTR tetramer and prevents tetramer dissociation by noncooperatively binding to the two thyroxine binding sites. Tafamidis is the first approved medicine for TTR-FAP. The Kd values for tafamidis for the two thyroxine binding sites on TTR, as determined by isothermal titration calorimetry, were 3 nM and 278 nM, respectively. In another in vitro study using wild type TTR, V30M mutant TTR, and V122I mutant TTR, it was shown that tafamidis inhibited fibril formation in a concentration-dependent manner reaching EC₅₀ at a tafamidis:TTR stoichiometry of <1 (EC₅₀ was in the range of 2.7–3.2 μM, corresponding to a tafamidis:TTR stoichiometry range of 0.75–0.9). Tafamidis has been synthesized by coupling 4-amino-3- hydroxybenzoic acid with 3,5-dichlorobenzoyl chloride followed by dehydration using p-toluenesulfonic acid.

Originator

Scripps Research Institute (United States)

The Uses of Tafamidis Meglumine

Tafamidis Meglumine is used as a potential therapeutics for COVID-19 and related viral infections

Definition

ChEBI: Tafamidis meglumine is an organoammonium salt obtained by combining tafamidis with one molar equivalent of 1-deoxy-1-(methylamino)-D-glucitol. Used for the amelioration of transthyretin-related hereditary amyloidosis. It has a role as a central nervous system drug. It contains a tafamidis(1-).

brand name

Vyndaqel

Clinical Use

Tafamidis meglumine is a transthyretin amyloid inhibitor that was approved for the treatment of transthyretin amyloid polyneuropathy (ATTR-PN) and transthyretin familial amyloid polyneropathy (TTR-FAP). These diseases represent a rare autosomal neurodegenerative disorder characterized by autonomic, sensory and motor impairment which are typically fatal. Tafamidis was discovered at The Scripps Research Institute and developed by Pfizer.

Synthesis

Numerous synthetic routes have been reported including the use of direct CH activation to form the key biaryl bond. Although only reported on small scale, the most likely production route is detailed in the scheme.

Condensation of methyl 4-amino-3-hydroxybenzoic acid (154) with 3,5-dichlorobenzoyl chloride (155) in refluxing pyridine gave intermediate amide 156 which underwent cycylization upon treatment with p-TsOH in refluxing toluene producing benzoxazole 157. Saponification of the methyl ester with LiOH (aq.) afforded tafamidis. The free acid was treated with N-methyl-D-glutamine to provide tafamidis meglumine (XXIV) in 82% yield.