General
Preferred name
TAFAMIDIS
Synonyms
Fx-1006A ()
TAFAMIDIS MEGLUMINE ()
Vyndaqel ()
FX-1006 ()
FX-1005 ()
Vyndamax ()
FX1006 ()
FX-1006A ()
Tafamidis ()
P&D ID
PD046659
CAS
951395-08-7
594839-88-0
137464-18-7
Tags
available
drug
Approved by
PMDA
EMA
FDA
First approval
2019
2011
Drug Status
investigational
approved
Max Phase
Phase 4
Probe control
Probe control not defined
Orthogonal probes
0
No orthogonal probes found
Similar probes
0
No structurally similar probes found
Structure
P&D probe-likeness score
Structure formats
[[ format ]]
[[ compound[format === 'MOL' ? 'molblock' : format.toLowerCase()] ]]
Description
(extracted from source data)
DESCRIPTION
Tafamidis binds potently and selectively to transthyretin (TTR), stabilising protein tetramers, thereby inhibiting the formation of amyloid fibrils . The trade name for this drug is Vyndaqel which contains tafamidis meglumine (PubChem CID 24970412).
INDICATION
**Indicated** for:; ; 1) The treatment of transthyretin amyloidosis in adult patients with stage 1 symptomatic polyneuropathy to delay peripheral neurologic impairment in Europe.[L6247] ; ; 2) The treatment of cardiomyopathy in wild type or hereditary transthyretin-mediated amyloidosis in the US.[label]; ; There is a distinction in dosage between tafamidis, dosed at 61mg daily, and tafamadis meglumine which is dosed at 80mg daily.
TOXICITY
The most common adverse effects associated with taking tafamidis include urinary tract infection, vaginal infection, diarrhea, and upper abdominal pain [FDA Label].; ; No cases of acute overdose have yet been reported [FDA Label]. In clinical trials of healthy volunteers, the highest dose of tafamidis administrated was 480 mg in a single dose and 60 mg once daily for two weeks [FDA Label]. The reported treatment-related adverse events were mild to moderate and included headache, somnolence, myalgia, insomnia, hordeolum, photosensitivity reaction, and presyncope [FDA Label].
DESCRIPTION
Tafamidis binds potently and selectively to transthyretin (TTR), stabilising protein tetramers, thereby inhibiting the formation of amyloid fibrils . The trade name for this drug is Vyndaqel which contains tafamidis meglumine (PubChem CID 24970412). The Vyndamax brand contains tafamidis parent molecule.
(GtoPdb)
PHARMACODYNAMICS
Transthyretin (TTR), also referred to as prealbumin, is an endogenous, soluble, beta-sheet rich, 127-amino acid, non-glycosylated protein that is largely synthesized and secreted into the blood flow by the liver [A27206]. This TTR circulates in the blood flow primarily in a tetramer configuration with only a very small amount of dissociated monomer [A27206]. In the blood, TTR tetramer main functions generally revolve around binding retinol-binding protein bound to retinol (holo-retinol-binding protein) and a small amount of thyroxine, followed by transporting these substances to tissues [A27206]. TTR tetramer consequently possesses two distinct dimer-dimer interfaces, the less stable of which comprises two highly conserved thyroxine binding sites [A27206]. Despite possessing the ability to bind and transport thyroxine, less than 10% of the thyroxine in blood is bound to TTR, leaving more than 99% of the thyroxine binding sites in TTR unbound [A27206].; ; Tafamidis is consequently a rationally designed, non-NSAID benzoxazole derivative that specifically binds with high affinity and selectivity to the two typically vacant thyroxine binding sites on the native tetrameric form of TTR and functions to kinetically stabilize the tetramer, slowing monomer formation, misfolding, and amyloidogenesis [A27206]. Given this rational design, tafamidis demonstrates effective target specificity, resulting in a low-toxicity profile and good patient tolerance [A27206].; ; Nevertheless, TTR dissociation into monomers in TTR familial amyloid polyneuropathy (TTR-FAP) is a progressive illness, a condition whose worsening can only be slowed - and not cured - by tafamidis therapy. The only formal treatment that can halt the progress of TTR-FAP is a liver transplant. General complications associated with transplant surgery including the inherent possibility for complications arising either during or as a result of the transplant procedure as well as the subsequent need for successful transplant patients to take various immune system suppressants to prevent long-term transplant organ rejection contribute to the natural risk associated with a liver transplant.
MOA
Transthyretin (TTR) amyloid polyneuropathy (also known as TTR familial amyloid polyneuropathy, TTR-FAP) results from genetic mutations in the TTR gene that cause destabilization of ordinary TTR tetramers and/or speed up TTR tetramer dissociation into monomers [A27206]. TTR-FAP itself is a multi-faceted, progressive, axonal degenerative neuropathy characterized by sensory, motor, and autonomic impairment [FDA Label].; ; The dissociation of TTR tetramers to monomers is, in fact, the rate-limiting step in the pathogenesis of TTR-FAP [FDA Label]. The folded monomers that comprise ordinary TTR tetramers undergo partial denaturation to produce alternatively folded monomeric amyloidogenic intermediates [FDA Label]. These intermediates then misassemble into a variety of soluble oligomers, profilaments, filaments, and amyloid fibrils [FDA Label]. These various undesired, soluble aggregates subsequently deposit upon tissues where they ultimately are not expected to be present or needed [A27206]. In particular, studies demonstrating TTR's ability to influence nerve physiology by enhancing nerve regeneration in mouse models [A32598] emphasizes a potential function of TTR for nerve biology and repair that may assist in explaining why mutant TTR aggregrates preferentially deposit in the peripheral nervous system of patients with TTR-FAP [A27206].; ; Tafamidis is subsequently a rationally designed pharmaceutical that specifically binds non-cooperatively to the two thyroxine binding sites on the native tetrameric form of TTR to prevent its dissociation into monomers [FDA Label]. Tafamidis is consequently formally considered to be a specific stabilizer of TTR, and its inhibition of TTR tetramer dissociation forms the rationale for its use as a treatment to slow - but not cure - the disease progression of TTR-FAP [FDA Label].
[[ p.pathway_name ]]
[[ compound.targets[tid].gene_name ]]
Compound Sets
22
Cayman Chemical Bioactives
ChEMBL Approved Drugs
ChEMBL Drugs
Concise Guide to Pharmacology 2021/22
Concise Guide to Pharmacology 2023/24
Drug Repurposing Hub
DrugBank
DrugBank Approved Drugs
DrugCentral
DrugCentral Approved Drugs
Enamine BioReference Compounds
EU-OPENSCREEN Bioactive Compound Library
Guide to Pharmacology
IPPI - DB
Mcule NIBR MoA Box Subset
NCATS Inxight Approved Drugs
Novartis Chemogenetic Library (NIBR MoA Box)
ReFrame library
Selleckchem Bioactive Compound Library
[[ a.name ]]
[[ ligand_id ]]
free of charge
External IDs
50
Molecular Weight
306.98
Hydrogen Bond Acceptors
3
Hydrogen Bond Donors
1
Rotatable Bonds
2
Ring Count
3
Aromatic Ring Count
3
cLogP
4.5
TPSA
63.33
Fraction CSP3
0.0
Chiral centers
0.0
Largest ring
6.0
QED
0.76
Structural alerts
0
No structural alerts detected
Related compounds
Custom attributes
(extracted from source data)
Member status
member
MOA
Transthyretin tetramer stabilizer
transthyretin amyloid inhibitor
Indication
familial amyloid polyneuropathy (FAP)
Target
TTR
Transthyretin (TTR)
5-HT Receptor
Pathway
Neuronal Signaling
Source data
