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Tafamidis

Tafamidis structure

CAS No:
594839-88-0
Formula:
C14H7Cl2NO3
Chemical Name:
Tafamidis
Synonyms:
6-Benzoxazolecarboxylic acid,2-(3,5-dichlorophenyl)-;2-(3,5-Dichlorophenyl)-6-benzoxazolecarboxylic acid;Fx 1006;Tafamidis;Vyndamax;2-(3,5-Dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid
Categories:
Active Pharmaceutical Ingredients > Other Chemical Drugs

Description

Tafamidis(Fx1006A) is a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascade.Target: OthersTafamidis is a drug for the amelioration of transthyretin-related hereditary amyloidosis.Tafamidis functions by kinetic stabilization of the correctly folded tetrameric form of the transthyretin (TTR) protein. Tafamidis binds selectively and with negative cooperativity (K(d)s ~2 nM and ~200 nM) to the two normally unoccupied thyroxine-binding sites of the tetramer

Tafamidis is 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 amyloidosis. It has a role as a central nervous system drug. It is a member of 1,3-benzoxazoles, a monocarboxylic acid and a dichlorobenzene. It is a conjugate acid of a tafamidis(1-).|Tafamidis and tafamidis meglumine (FX-1006A) are benzoxazole derivatives developed by FoldRX. Tafamidis is structurally similar to diflusinal. Tafamidis was granted an EMA market authorisation on 16 November 2011 and FDA approval on 3 May 2019.

Tafamidis Basic Attributes

Molecular Weight：

308.12

Exact Mass：

308.12

UNII：

8FG9H9D31J

DSSTox ID：

DTXSID00208185

ATC Code：

N07XX08|N - Nervous system

Characteristics

PSA：

63.3

XLogP3：

4.2

Density：

1.5±0.1 g/cm3

Flash Point：

248.1±27.3 °C

Refractive Index：

1.677

Water Solubility：

>50mg/mL

Safety Information

Precautionary statement(s)：

P201, P202, P261, P264, P271, P280, P281, P302+P352, P304+P340, P305+P351+P338, P308+P313, P312, P321, P332+P313, P337+P313, P362, P403+P233, P405, P501

Hazard Statements：

H315

GHS Classification：

|Danger|H315 (50%): Causes skin irritation [Warning Skin corrosion/irritation]|P201, P202, P261, P264, P271, P280, P281, P302+P352, P304+P340, P305+P351+P338, P308+P313, P312, P321, P332+P313, P337+P313, P362, P403+P233, P405, and P501|Aggregated GHS information provided by 5 companies from 4 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Toxicity

Toxicity Summary：

Data regarding overdoses of tafamidis are not readily available. In a clinical trial, some patients were given up to 6 times the normal dose with one reported case of mild hordeolum.

Protein Binding：

Tafamidis 99.9% protein bound in plasma, mostly to transthyretin.

Drug Information

Drug Indication：

Tafamidis is indicated to treat cardiomyopathy of wild type or hereditary transthyretin-mediated amyloidosis in adults.|FDA Label|Vyndaqel is indicated for the treatment of transthyretin amyloidosis in adult patients with stage-1 symptomatic polyneuropathy to delay peripheral neurologic impairment.

Pharmacology：

Tafamidis stabilizes transthyretin tetramers, reducing the amount of monomers available for amyloidogenesis. It has a long duration of action as it is given once daily, and a wide therapeutic window.

Absorption：

Tafamidis reaches a C_max of 1430.93ng/mL with a T_max of 1.75h fasted and 4h fed. The AUC of tafamidis is 47,864.31ng\*h/mL.|A 20mg oral dose of tafamidis is approximately 59% recovered in the feces, largely as unchanged drug. Approximately 22% of a 20mg oral dose is recovered in the urine, mostly as the glucuronide metabolite.|The apparent volume of distribution at steady state is 18.5L.|The oral clearance of tafamidis is 0.263L/h. The apparent total clearance is 0.44L/h.

Metabolism/Metabolites：

Tafamidis is largely not subject to first pass or oxidative metabolism, being 90% unchanged after in in vitro experiments. Preclinical data suggest tafamidis is mainly metabolized through glucuronidation and excreted in bile.

Biological Half-Life：

The half life of tafamidis is 49h.

Mechanism of Action：

Genetic mutations or natural misfolding of transthyretin destabalizes transthyretin tetramers, leading to their dissociation and aggregation in tissues, and disrupting the normal function of these tissues. Tafamidis binds to transthyretin tetramers at the thyroxin binding sites, stabilizing the tetramer, reducing the availability of monomers for amyloidogenesis.

MeSH Entry Terms：

FX 1006A

Tafamidis Use and Manufacturing

Uses

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).

Use Classification：

Human drugs -> Orphan -> Vyndaqel -> EMA Drug Category|Other nervous system drugs -> Human pharmacotherapeutic group|Human drugs -> Rare disease (orphan)|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients

Computed Properties

Molecular Weight:308.1
XLogP3:4.2
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:2
Exact Mass:306.9802985
Monoisotopic Mass:306.9802985
Topological Polar Surface Area:63.3
Heavy Atom Count:20
Complexity:371
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes

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