- Effects of 18F-fluorinated neopentyl glycol side-chain on the biological characteristics of stilbene amyloid-β PET ligands
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Introduction: The 2,2-dihydroxymethyl-1-[18F]fluoropropane group, also called 18F-labelled neopentyl glycol side-chain, is a novel 18F-labelling group for positron emission tomography (PET) imaging agents. The aim of using this group is to develop simple purification with solid-phase extraction without high-performance liquid chromatography. However, the effects of the neopentyl 18F-labelling group on the characteristics of brain imaging agents are unknown. Here, we added this side-chain to compounds with an aminostilbene structure to evaluate their effects on the biological properties of aminostilbene as an amyloid-β (Aβ) radioligand. Methods: Biodistributions of four novel 18F-labelled stilbene compounds with different lengths of polyethylene glycol (PEG) linkers, called [18F]Cpd-0, -1, -2, and -4, (PEG = 0, 1, 2, and 4), and [18F]AV-1 in normal mice were evaluated. Metabolite analysis of [18F]Cpd-0 and -1 was performed with mouse plasma and brain. A competitive binding assay of [18F]AV-1 binding to Aβ1–42 fibrils was performed to determine the binding properties of the compounds. Results: [18F]Cpd-0, -1, and -2 demonstrated moderate initial brain uptake in mice (3.1–4.2% injected dose/g at 2 min post-injection) followed by fast clearance, and in vivo defluorination of these compounds was negligible. [18F]Cpd-4 exhibited low brain uptake and high bone uptake. Compared with [18F]Cpd-1, the percentage of [18F]Cpd-0 in mouse brain was high at 10 min post-injection. A competitive binding assay revealed partial interference effects by the neopentyl glycol side-chain on binding of stilbene compounds to Aβ1–42 fibrils. Conclusions: Aminostilbene compounds with two or fewer PEG linkers containing an 18F-labelled neopentyl glycol side-chain demonstrated preferable pharmacokinetic properties as a brain imaging radioligand in normal mice. These side-chains can be used as an alternative labelling group for imaging agents targeting the brain.
- Tago, Tetsuro,Toyohara, Jun,Fujimaki, Ryo,Tatsuta, Maho,Song, Ruichong,Hirano, Keiichi,Iwai, Kumiko,Tanaka, Hiroshi
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- POLYCYCLIC COMPOUNDS AND METHODS FOR THE TARGETED DEGRADATION OF RAPIDLY ACCELERATED FIBROSARCOMA POLYPEPTIDES
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The present disclosure relates to bifunctional compounds, ULM— L—PTM, which find utility as modulators of Rapidly Accelerated Fibrosarcoma (RAF, such as c-RAF, A- RAF and/or B-RAF; the target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hippel-Lindau, cereblon, Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand which binds to the respective E3 ubiquitin ligase and on the other end a moiety which binds the target protein RAF, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein, or the constitutive activation of the target protein, are treated or prevented with compounds and compositions of the present disclosure.
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Paragraph 0522; 0523
(2020/03/29)
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- IRAK4 INHIBITORS AND USES THEREOF
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Compounds of Formula I as IRAK4 inhibitors are disclosed. The pharmaceutical compositions comprising compounds of formula I, methods of synthesis of these compounds, methods of treatment for diseases associated with IRAK-4 such as inflammatory diseases an
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Paragraph 0136; 0141
(2019/05/22)
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- N2-(2-METHOXYPHENYL)PYRIMIDINE DERIVATIVE, METHOD FOR PREPARING SAME, AND PHARMACEUTICAL COMPOSITION FOR CANCER PREVENTION OR TREATMENT CONTAINING SAME AS ACTIVE INGREDIENT
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The present invention relates to a N2-(2-methoxyphenyl)pyrimidine derivative, a preparation method thereof, and a pharmaceutical composition for the prevention or treatment of cancer comprising the same as an active ingredient. The N2-(2-methoxyphenyl)pyrimidine derivative, the optical isomer thereof, or the pharmaceutically acceptable salt thereof of the present invention is very effective in suppressing anaplastic lymphoma kinase (ALK) activity and as a result it can improve the effectiveness of treatment on cancer cells having anaplastic lymphoma kinase (ALK) fusion proteins such as EML4-ALK and NPM-ALK, so that it can be effectively used as a pharmaceutical composition for preventing or treating cancer.
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Paragraph 0250; 0251; 0252
(2018/05/03)
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- COMPOUNDS AND METHODS FOR THE TARGETED DEGRADATION OF RAPIDLY ACCELERATED FIBROSARCOMA POLYPEPTIDES
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The present disclosure relates to bifunctional compounds, which find utility as modulators of Rapidly Accelerated Fibrosarcoma (RAF, such as c-RAF, A-RAF and/or B-RAF; the target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hippel-Lindau, cereblon, Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand which binds to the respective E3 ubiquitin ligase and on the other end a moiety which binds the target protein RAF, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein, or the constitutive activation of the target protein, are treated or prevented with compounds and compositions of the present disclosure.
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Paragraph 1250
(2018/07/15)
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- THIAZOLIDINONE COMPOUNDS AND USE THEREOF
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A pharmaceutical composition containing a compound of Formula (I) for treating an opioid receptor-associated condition. Also disclosed is a method for treating an opioid receptor-associated condition using such a compound. Further disclosed are two sets of thiazolidinone compounds of formula (I): (i) compounds each having an enantiomeric excess greater than 90% and (ii) compounds each being substituted with deuterium.
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Paragraph 0966-0967
(2017/09/21)
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- Synthesis of bicyclic enediynes that possess a photosensitive triggering device and exhibit strong DNA cleaving activity
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The synthesis of a bicyclic enediyne capable of photosensitive triggering and conjugated to a pyrrole-imidazole polyamide is described. Using UV irradiation, this hybrid molecule is shown to exhibit 100-fold stronger potency for DNA cleavage, in an in vitro assay, as compared to the enediyne without the DNA-localizing pyrrole-imidazole.
- Tanaka, Hiroshi,Tanaka, Yoshikazu,Minoshima, Masafumi,Yamaguchi, Sho,Fuse, Shinichiro,Doi, Takayuki,Kawauchi, Susumu,Sugiyama, Hiroshi,Takahashi, Takashi
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supporting information; experimental part
p. 5942 - 5944
(2010/10/21)
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- Regioselective alkylation of hydroxysalicylaldehydes
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Schiff-base ligands are often used as backbone ligands for mono- and dinuclear complexes that serve as catalysts during aerobic oxidation reactions. However, their water solubility is low and limits their applicability as catalysts to transform highly water-soluble biomolecules, such as carbohydrates or amino alcohols. A new method to regioselectively incorporate water solubility-promoting polyethylene glycol side chains into a frequently used aldehyde building block of Schiff-base ligands has been developed.
- Gichinga, Moses G.,Striegler, Susanne
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supporting information; experimental part
p. 4917 - 4922
(2009/10/02)
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- Basket-shaped hosts with semi-flexible handles
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Basket-shaped hosts were synthesized starting from the concave building block 4: .To this end, oligo(oxyethylene)bridges, containing different aromatic rings, were attached to the 3,6- and 3',6'-positions of the xylylene rings of 4.These bridges include 5,6-benzo-1,4,7,10-tetraoxadec-5-ene, 5,6,7-benzo-1,4,8,11-tetraoxaundeca-5,6-diene, 5,6-(2,3-naphtho)-1,4,7,10-tetraoxa-dec-5-ene, 8,9-benzo-1,4,7,10,13,16-hexaoxahexadec-8-ene and 8,9-(2,3-naphtho)-1,4,7,10,13,16-hexaoxahexadec-8-ene chains.Alkali-metal ions and protonated aliphatic or aromatic diamines are bound in these baskets in a 1:1 host/guest ratio.For the metal ions, a clamshell-like or a sandwich-like complex is proposed.Aliphatic diammonium guests are bound in such a way that the methylene chains are wedged in between the o-xylylene units of the host, as concluded from the upfield shifts observed in the 1H NMR spectra of the guest CH2 protons.Free energies of binding of the new hosts with nineteen guests were measured using the picrate extraction technique.The highest -ΔG0 values were obtained for the complexes with the diammonium salts (-ΔG0 values up to 13.4 kcal/mol).
- Smeets, J. W. H.,Visser, H. C.,Kaats-Richters, V. E. M.,Nolte, R. J. M.
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p. 147 - 153
(2007/10/02)
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