In patients with hereditary transthyretin amyloidosis (hATTR), treatment with the uricosuric agent benziodarone (BID) and its potential metabolite 6-hydroxybenziodarone (6-hydroxy BID) has demonstrated efficacy, according to findings from a pharmacokinetic study published in the journal Bioorganic & Medicinal Chemistry.

Amyloid deposition of the plasma protein transthyretin (TTR) is associated with progressive organ dysfunction among individuals, resulting in hATTR. In those with this progressive systemic disorder, amyloid fibrils of TTR accumulate in a number of organs and body systems, including the nerves, heart, kidneys, brain, eyes, and gastrointestinal tract.

Despite being a stable homotetrameric protein, the dissociation of TTR into misfolded monomers is linked to its aggregation into amyloid fibrils. Among patients with hATTR, the “rate limiting step of the amyloid aggregation is the dissociation of the native tetramer,” with “stabilization of the native tetramer” thus considered to be an effective strategy for averting the amyloid aggregation of TTR.

The researchers sought to evaluate the inhibitor activity of 3 clinically used drug molecules—that is, benzbromarone (BBM), BID, and amiodarone (AMD)—against the acid-induced aggregation of V30M-TTR in vitro in patients with hATTR.

Read more about experimental therapies for hATTR

Both BID and BBM are beneficial in treating hyperuricemia and gout. The agents exhibit a similar structure, with each displaying a benzofuran ring and a halogenated hydroxyphenyl ring. BID has 2 iodine atoms in its hydroxyphenyl ring, whereas BBM has 2 bromine rings in its hydroxyphenyl ring. In contrast, the structure of AMD is bulkier than the structures of BID and BBM, with AMD exhibiting a butyl group in the benzofuran ring and a diethylamino-ethoxy group in the diiodophenyl ring.

Based on results of an acid-induced aggregation assay, treatment with BID in patients with hATTR demonstrates strong inhibitor activity that is similar to that with treatment with tafamidis—the currently used therapeutic option in individuals with hATTR. In fact, use of the metabolite 6-hydroxy BID maintained the strong amyloid inhibitory activity associated with BID.

Study findings revealed that an ex vivo competitive binding assay that used a fluorogenic probe demonstrated the high potency of BID and 6-hydroxy BID for the selective binding to TTR in human plasma. Further, an analysis of an x-ray crystal demonstrated that the halogenated hydroxyphenyl ring was situated at the entrance of the thyroxine binding channel of TTR, with the BID ring located in the inner channel.

“The ex vivo competitive binding assay showed that BID had high potency for selective binding to TTR in human plasma,” the researchers explained. “Moreover, 6-hydroxy BID retained the high potency and selectivity of BID,” they noted. “These studies suggest that BID and 6-hydroxy BID would potentially be effective in patients with hATTR,” they concluded.


Mizuguchi M, Yokoyama T, Okada T, et al. Benziodarone and 6-hydroxybenziodarone are potent and selective inhibitors of transthyretin amyloidogenesis. Bioorg Med Chem. Published online June 9, 2023. doi:10.1016/j.bmc.2023.117370