Abstract:Therapeutic interventions are being developed for Huntington’s
disease (HD), a hallmark of which is mutant huntingtin protein (mHTT)
aggregates. Following the advancement to human testing of two [11C]-PET ligands for aggregated mHTT, attributes for further
optimization were identified. We replaced the pyridazinone ring of
CHDI-180 with a pyrimidine ring and minimized off-target binding using
brain homogenate derived from Alzheimer’s disease patients.
The major in vivo metabolic pathway via aldehyde
oxidase was… Show more
“…These include inhibitors of the MDM2–p53 protein–protein interaction for cancer 106 , MNK1/2 protein degraders for triple-negative breast cancer 107 , M pro inhibitors for COVID-19 (refs. 108 , 109 ), memantine analogues for Alzheimer disease 110 , dual TYK2/JAK1 inhibitors for autoimmune diseases 111 , 112 and PET ligands for Huntington disease 113 . Fig.…”
Section: Deuterium In De Novo Drug Discoverymentioning
Substitution of a hydrogen atom with its heavy isotope deuterium entails the addition of one neutron to a molecule. Despite being a subtle change, this structural modification, known as deuteration, may improve the pharmacokinetic and/or toxicity profile of drugs, potentially translating into improvements in efficacy and safety compared with the non-deuterated counterparts. Initially, efforts to exploit this potential primarily led to the development of deuterated analogues of marketed drugs through a ‘deuterium switch’ approach, such as deutetrabenazine, which became the first deuterated drug to receive FDA approval in 2017. In the past few years, the focus has shifted to applying deuteration in novel drug discovery, and the FDA approved the pioneering de novo deuterated drug deucravacitinib in 2022. In this Review, we highlight key milestones in the field of deuteration in drug discovery and development, emphasizing recent and instructive medicinal chemistry programmes and discussing the opportunities and hurdles for drug developers, as well as the questions that remain to be addressed.
“…These include inhibitors of the MDM2–p53 protein–protein interaction for cancer 106 , MNK1/2 protein degraders for triple-negative breast cancer 107 , M pro inhibitors for COVID-19 (refs. 108 , 109 ), memantine analogues for Alzheimer disease 110 , dual TYK2/JAK1 inhibitors for autoimmune diseases 111 , 112 and PET ligands for Huntington disease 113 . Fig.…”
Section: Deuterium In De Novo Drug Discoverymentioning
Substitution of a hydrogen atom with its heavy isotope deuterium entails the addition of one neutron to a molecule. Despite being a subtle change, this structural modification, known as deuteration, may improve the pharmacokinetic and/or toxicity profile of drugs, potentially translating into improvements in efficacy and safety compared with the non-deuterated counterparts. Initially, efforts to exploit this potential primarily led to the development of deuterated analogues of marketed drugs through a ‘deuterium switch’ approach, such as deutetrabenazine, which became the first deuterated drug to receive FDA approval in 2017. In the past few years, the focus has shifted to applying deuteration in novel drug discovery, and the FDA approved the pioneering de novo deuterated drug deucravacitinib in 2022. In this Review, we highlight key milestones in the field of deuteration in drug discovery and development, emphasizing recent and instructive medicinal chemistry programmes and discussing the opportunities and hurdles for drug developers, as well as the questions that remain to be addressed.
“…CHDI's achieved this by altering the CHDI-180R scaffold to include a fluorine-18 radiolabelling site, specifically adding tetra-deutero 2-fluoroethoxy group to reduce defluorination in their fluorine-18 candidate [ 18 F]CHDI-650. [45] The 2fluoroethoxy is a common functional group employed to introduce fluorine-18 into ligands owing to its modularity, however this chemical group is prone to defluorination in vivo. This is undesirable owing to the high oxaphilicity of fluoride anions, which leads to skull uptake.…”
Section: Chdi and Mhtt Pet Ligand Developmentmentioning
Positron emission tomography imaging of misfolded proteins with high‐affinity and selective radioligands has played a vital role in expanding our knowledge of neurodegenerative diseases such as Parkinson's and Alzheimer's disease. The pathogenesis of Huntington's disease, a CAG trinucleotide repeat disorder, is similarly linked to the presence of protein fibrils formed from mutant huntingtin (mHTT) protein. Development of mHTT fibril–specific radioligands has been limited by the lack of structural knowledge around mHTT and a dearth of available hit compounds for medicinal chemistry refinement. Over the past decade, the Cure Huntington's Disease Initiative (CHDI), a non‐for‐profit scientific management organisation has orchestrated a large‐scale screen of small molecules to identify high affinity ligands of mHTT, with lead compounds now reaching clinical maturity. Here we describe the mHTT radioligands developed to date and opportunities for further improvement of this radiotracer class.
“…It turned out to be possible to use Pittsburgh compound B [ 178 , 179 , 180 ] and the FDA-approved radiopharmaceuticals [ 18 F]flutemetamol [ 181 ], [ 18 F]florbetapir [ 182 , 183 ], and [ 18 F]florbetaben [ 184 ] for PET diagnostics of systemic immunoglobulin light chain (AL) amyloidosis and hereditary transthyretin amyloidosis. In a recent series of works [ 185 , 186 , 187 ], the novel PET ligands [ 11 C]CHDI-180, [ 11 C]CHDI-626, and [ 18 F]CHDI-650 ( Figure 27 ) were designed to bind huntingtin protein fibrils in the brain in order to diagnose Huntington’s disease (HD). The design started from screening a collection of analogs of beta-amyloid binders, followed by an empirical exploration of the structure−activity relationships to increase the affinity and selectivity of binding to huntingtin fibrils relative to the Aβ fibrils in order to discriminate between HD and AD.…”
Section: Molecular Design Of Mri Fibril-binding Probesmentioning
The ability to detect and monitor amyloid deposition in the brain using non-invasive imaging techniques provides valuable insights into the early diagnosis and progression of Alzheimer’s disease and helps to evaluate the efficacy of potential treatments. Magnetic resonance imaging (MRI) is a widely available technique offering high-spatial-resolution imaging. It can be used to visualize amyloid deposits with the help of amyloid-binding diagnostic agents injected into the body. In recent years, a number of amyloid-targeted MRI probes have been developed, but none of them has entered clinical practice. We review the advances in the field and deduce the requirements for the molecular structure and properties of a diagnostic probe candidate. These requirements make up the base for the rational design of MRI-active small molecules targeting amyloid deposits. Particular attention is paid to the novel cryo-EM structures of the fibril aggregates and their complexes, with known binders offering the possibility to use computational structure-based design methods. With continued research and development, MRI probes may revolutionize the diagnosis and treatment of neurodegenerative diseases, ultimately improving the lives of millions of people worldwide.
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