tafamidis and Alzheimer-Disease

Amyloidosis is a group of diseases that includes Alzheimer's disease, prion diseases, transthyretin (ATTR) amyloidosis, and immunoglobulin light chain (AL) amyloidosis. The mechanism of organ dysfunction resulting from amyloidosis has been a topic of debate. This review focuses on the ultrastructure of tissue damage resulting from amyloid deposition and therapeutic insights based on the pathophysiology of amyloidosis. Studies of nerve biopsy or cardiac autopsy specimens from patients with ATTR and AL amyloidoses show atrophy of cells near amyloid fibril aggregates. In addition to the stress or toxicity attributable to amyloid fibrils themselves, the toxicity of non-fibrillar states of amyloidogenic proteins, particularly oligomers, may also participate in the mechanisms of tissue damage. The obscuration of the basement and cytoplasmic membranes of cells near amyloid fibrils attributable to an affinity of components constituting these membranes to those of amyloid fibrils may also play an important role in tissue damage. Possible major therapeutic strategies based on pathophysiology of amyloidosis consist of the following: (1) reducing or preventing the production of causative proteins; (2) preventing the causative proteins from participating in the process of amyloid fibril formation; and/or (3) eliminating already-deposited amyloid fibrils. As the development of novel disease-modifying therapies such as short interfering RNA, antisense oligonucleotide, and monoclonal antibodies is remarkable, early diagnosis and appropriate selection of treatment is becoming more and more important for patients with amyloidosis.

Topics: Alzheimer Disease; Amyloid; Amyloid Neuropathies, Familial; Benzoxazoles; Diflunisal; Humans; Immunoglobulin Light Chains; Immunoglobulin Light-chain Amyloidosis; Immunologic Factors; Myocardium; Neuroprotective Agents; Oligonucleotides; Peripheral Nerves; Prealbumin; Prion Diseases; RNA, Small Interfering

Transthyretin (TTR) has a well-established role in neuroprotection in Alzheimer's Disease (AD). We have setup a drug discovery program of small-molecule compounds that act as chaperones enhancing TTR/Amyloid-beta peptide (Aβ) interactions. A combination of computational drug repurposing approaches and in vitro biological assays have resulted in a set of molecules which were then screened with our in-house validated high-throughput screening ternary test. A prioritized list of chaperones was obtained and corroborated with ITC studies. Small-molecule chaperones have been discovered, among them our lead compound Iododiflunisal (IDIF), a molecule in the discovery phase; one investigational drug (luteolin); and 3 marketed drugs (sulindac, olsalazine and flufenamic), which could be directly repurposed or repositioned for clinical use. Not all TTR tetramer stabilizers behave as chaperones in vitro. These chemically diverse chaperones will be used for validating TTR as a target in vivo, and to select one repurposed drug as a candidate to enter clinical trials as AD disease-modifying drug.

Topics: Alzheimer Disease; Calorimetry; Dose-Response Relationship, Drug; Drug Discovery; Humans; Models, Molecular; Molecular Chaperones; Molecular Structure; Prealbumin; Small Molecule Libraries; Software; Structure-Activity Relationship

CHI's 17th International Tri-Conference on Molecular Medicine, held in San Francisco, included topics covering new developments in the field of medicinal chemistry. This conference report highlights selected presentations on fragment-based drug discovery, quantum mechanical energy decomposition for the analysis of SARs, medicinal chemistry strategies and the role of imaging in drug discovery. Investigational drugs discussed include MLN-4924 (Millennium Pharmaceuticals Inc), GDC-0449 (Chugai Pharmaceutical Co Ltd/Curis Inc/F Hoffmann-La Roche Ltd/Genentech Inc/NCI), RDEA-119 (Ardea Biosciences Inc/Bayer HealthCare AG) and tafamidis (Fx-1006A; FoldRx Pharmaceuticals Inc).

Topics: Alzheimer Disease; Amyloidosis; Anilides; Animals; Benzoxazoles; Chemistry, Pharmaceutical; Drug Discovery; Drug-Related Side Effects and Adverse Reactions; Enzyme Inhibitors; HSP90 Heat-Shock Proteins; Humans; Macrocyclic Compounds; Neoplasms; Pharmacokinetics; Positron-Emission Tomography; Pyridines; Quantum Theory; Receptors, Immunologic; Receptors, Prostaglandin; Structure-Activity Relationship