idarucizumab and Amyloid-Neuropathies--Familial

idarucizumab has been researched along with Amyloid-Neuropathies--Familial* in 2 studies

Other Studies

2 other study(ies) available for idarucizumab and Amyloid-Neuropathies--Familial

Article	Year
Identification of Transthyretin Tetramer Kinetic Stabilizers That Are Capable of Inhibiting the Retinol-Dependent Retinol Binding Protein 4-Transthyretin Interaction: Potential Novel Therapeutics for Macular Degeneration, Transthyretin Amyloidosis, and Th Journal of medicinal chemistry, 2021, 07-08, Volume: 64, Issue:13 Dissociation of transthyretin (TTR) tetramers may lead to misfolding and aggregation of proamyloidogenic monomers, which underlies TTR amyloidosis (ATTR) pathophysiology. ATTR is a progressive disease resulting from the deposition of toxic fibrils in tissues that predominantly presents clinically as amyloid cardiomyopathy and peripheral polyneuropathy. Ligands that bind to and kinetically stabilize TTR tetramers prohibit their dissociation and may prevent ATTR onset. Drawing from clinically investigated AG10, we designed a constrained congener ( Topics: Amyloid Neuropathies, Familial; Animals; Dose-Response Relationship, Drug; Kinetics; Mice; Mice, Inbred BALB C; Mice, Knockout; Molecular Structure; Prealbumin; Retinol-Binding Proteins, Plasma; Structure-Activity Relationship	2021
Enthalpy-Driven Stabilization of Transthyretin by AG10 Mimics a Naturally Occurring Genetic Variant That Protects from Transthyretin Amyloidosis. Journal of medicinal chemistry, 2018, 09-13, Volume: 61, Issue:17 Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) is a fatal disease with no available disease-modifying therapies. While pathogenic TTR mutations (TTRm) destabilize TTR tetramers, the T119M variant stabilizes TTRm and prevents disease. A comparison of potency for leading TTR stabilizers in clinic and structural features important for effective TTR stabilization is lacking. Here, we found that molecular interactions reflected in better binding enthalpy may be critical for development of TTR stabilizers with improved potency and selectivity. Our studies provide mechanistic insights into the unique binding mode of the TTR stabilizer, AG10, which could be attributed to mimicking the stabilizing T119M variant. Because of the lack of animal models for ATTR-CM, we developed an in vivo system in dogs which proved appropriate for assessing the pharmacokinetics-pharmacodynamics profile of TTR stabilizers. In addition to stabilizing TTR, we hypothesize that optimizing the binding enthalpy could have implications for designing therapeutic agents for other amyloid diseases. Topics: Administration, Oral; Amyloid Neuropathies, Familial; Animals; Benzoates; Biomimetics; Dogs; Entropy; Female; Humans; Male; Models, Molecular; Mutation; Prealbumin; Protein Conformation; Protein Stability; Pyrazoles; Serum Albumin, Human; Thermodynamics	2018

Article

Year

Identification of Transthyretin Tetramer Kinetic Stabilizers That Are Capable of Inhibiting the Retinol-Dependent Retinol Binding Protein 4-Transthyretin Interaction: Potential Novel Therapeutics for Macular Degeneration, Transthyretin Amyloidosis, and Th

Journal of medicinal chemistry, 2021, 07-08, Volume: 64, Issue:13

Dissociation of transthyretin (TTR) tetramers may lead to misfolding and aggregation of proamyloidogenic monomers, which underlies TTR amyloidosis (ATTR) pathophysiology. ATTR is a progressive disease resulting from the deposition of toxic fibrils in tissues that predominantly presents clinically as amyloid cardiomyopathy and peripheral polyneuropathy. Ligands that bind to and kinetically stabilize TTR tetramers prohibit their dissociation and may prevent ATTR onset. Drawing from clinically investigated AG10, we designed a constrained congener (

Topics: Amyloid Neuropathies, Familial; Animals; Dose-Response Relationship, Drug; Kinetics; Mice; Mice, Inbred BALB C; Mice, Knockout; Molecular Structure; Prealbumin; Retinol-Binding Proteins, Plasma; Structure-Activity Relationship

2021

Enthalpy-Driven Stabilization of Transthyretin by AG10 Mimics a Naturally Occurring Genetic Variant That Protects from Transthyretin Amyloidosis.

Journal of medicinal chemistry, 2018, 09-13, Volume: 61, Issue:17

Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) is a fatal disease with no available disease-modifying therapies. While pathogenic TTR mutations (TTRm) destabilize TTR tetramers, the T119M variant stabilizes TTRm and prevents disease. A comparison of potency for leading TTR stabilizers in clinic and structural features important for effective TTR stabilization is lacking. Here, we found that molecular interactions reflected in better binding enthalpy may be critical for development of TTR stabilizers with improved potency and selectivity. Our studies provide mechanistic insights into the unique binding mode of the TTR stabilizer, AG10, which could be attributed to mimicking the stabilizing T119M variant. Because of the lack of animal models for ATTR-CM, we developed an in vivo system in dogs which proved appropriate for assessing the pharmacokinetics-pharmacodynamics profile of TTR stabilizers. In addition to stabilizing TTR, we hypothesize that optimizing the binding enthalpy could have implications for designing therapeutic agents for other amyloid diseases.

Topics: Administration, Oral; Amyloid Neuropathies, Familial; Animals; Benzoates; Biomimetics; Dogs; Entropy; Female; Humans; Male; Models, Molecular; Mutation; Prealbumin; Protein Conformation; Protein Stability; Pyrazoles; Serum Albumin, Human; Thermodynamics

2018