Synthesis and SAR study of new thiazole derivatives as vascular adhesion protein-1 (VAP-1) inhibitors for the treatment of diabetic macular edema

Inoue, Takayuki; Morita, Masataka; Tojo, Takashi; Yoshihara, Kousei; Nagashima, Akira; Moritomo, Ayako; Ohkubo, Mitsuru; Miyake, Hiroshi

doi:10.1016/j.bmc.2012.12.025

Cited by 16 publications

(11 citation statements)

References 21 publications

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“…S2). Exposure of compound 2 to trifluoroacetic acid (TFA) in dichloromethane and subsequent concentration of the reaction mixture gave a crude amine salt, which was then coupled with N-(5-formylthiazol-2-yl)acetamide (compound 3) under the action of sodium triacetoxyborohydride (32). This reductive amination protocol delivered the target molecule LSN3316612 in 75% yield over two steps (fig.…”

Section: Synthesis Of Lsn3316612 and Radioligand Precursorsmentioning

confidence: 99%

PET ligands [ ¹⁸ F]LSN3316612 and [ ¹¹ C]LSN3316612 quantify O -linked-β- N -acetyl-glucosamine hydrolase in the brain

Haskali

Ruley

et al. 2020

Sci. Transl. Med.

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We aimed to develop effective radioligands for quantifying brain O-linked-β-N-acetyl-glucosamine (O-GlcNAc) hydrolase (OGA) using positron emission tomography in living subjects as tools for evaluating drug target engagement. Posttranslational modifications of tau, a biomarker of Alzheimer’s disease, by O-GlcNAc through the enzyme pair OGA and O-GlcNAc transferase (OGT) are inversely related to the amounts of its insoluble hyperphosphorylated form. Increase in tau O-GlcNAcylation by OGA inhibition is believed to reduce tau aggregation. LSN3316612, a highly selective and potent OGA ligand [half-maximal inhibitory concentration (IC50) = 1.9 nM], emerged as a lead ligand after in silico analysis and in vitro evaluations. [3H]LSN3316612 imaged and quantified OGA in postmortem brains of rat, monkey, and human. The presence of fluorine and carbonyl functionality in LSN3316612 enabled labeling with positron-emitting fluorine-18 or carbon-11. Both [18F]LSN3316612 and [11C]LSN3316612 bound reversibly to OGA in vivo, and such binding was blocked by pharmacological doses of thiamet G, an OGA inhibitor of different chemotype, in monkeys. [18F]LSN3316612 entered healthy human brain avidly (~4 SUV) without radiodefluorination or adverse effect from other radiometabolites, as evidenced by stable brain total volume of distribution (VT) values by 110 min of scanning. Overall, [18F]LSN3316612 is preferred over [11C]LSN3316612 for future human studies, whereas either may be an effective positron emission tomography radioligand for quantifying brain OGA in rodent and monkey.

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Section: Synthesis Of Lsn3316612 and Radioligand Precursorsmentioning

confidence: 99%

PET ligands [ ¹⁸ F]LSN3316612 and [ ¹¹ C]LSN3316612 quantify O -linked-β- N -acetyl-glucosamine hydrolase in the brain

Haskali

Ruley

et al. 2020

Sci. Transl. Med.

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“…Mechanism-based, 34 nM 2C11 GOLD 5.0 [80] Mechanism-based, 0.23 µM 2C11 GOLD 5.0 [79] Interacting residues: Covalent bond between guanidine group and TPQ; H-bond between guanidine group and D386; S-O interaction of sulfur atom in the thiazole ring with T210 backbone carbonyl oxygen; proton-π interaction of amide moiety with Y176.…”

Section: R6: Compound 35amentioning

confidence: 99%

“…Inoue et al [79] identified a thiazole hit compound with an IC50 value of 3.5 µM for hVAP-1 inhibition using high-throughput screening (HTS) and structure-activity relationship (SAR) studies. The developed thiazole compounds have a guanidine moiety that mimics a substrate Schiff base intermediate complex with TPQ.…”

Section: Thiazolesmentioning

confidence: 99%

“…Inoue et al [81] continued their earlier work with thiazole compounds (4.2.2) intending to design compounds that bind better to hVAP-1, as the developed compound R5 [79] was a much better inhibitor of rat than hVAP-1. They first used the thiazole pharmacophore of compound R5 (named 2 in [81]) and optimized the phenylguanidine biostere, 1H-benzimidazol-2-amine (compound R8) to design compound R9 by synthesis and SAR of 1H-imidazol-2-amines compounds.…”

Section: H-imidazol-2-aminesmentioning

confidence: 99%

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Human Copper-Containing Amine Oxidases in Drug Design and Development

et al. 2020

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Two members of the copper-containing amine oxidase family are physiologically important proteins: (1) Diamine oxidase (hDAO; AOC1) with a preference for diamines is involved in degradation of histamine and (2) Vascular adhesion protein-1 (hVAP-1; AOC3) with a preference for monoamines is a multifunctional cell-surface receptor and an enzyme. hVAP-1-targeted inhibitors are designed to treat inflammatory diseases and cancer, whereas the off-target binding of the designed inhibitors to hDAO might result in adverse drug reactions. The X-ray structures for both human enzymes are solved and provide the basis for computer-aided inhibitor design, which has been reported by several research groups. Although the putative off-target effect of hDAO is less studied, computational methods could be easily utilized to avoid the binding of VAP-1-targeted inhibitors to hDAO. The choice of the model organism for preclinical testing of hVAP-1 inhibitors is not either trivial due to species-specific binding properties of designed inhibitors and different repertoire of copper-containing amine oxidase family members in mammalian species. Thus, the facts that should be considered in hVAP-1-targeted inhibitor design are discussed in light of the applied structural bioinformatics and structural biology approaches.

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“…19 These derivatives continue to attract the attention of biologists because of their widespread use in the treatment of the biological systems. For instance, many papers have been published on the use of these compounds exhibiting antimicrobial, [20][21][22] antifungal and anti-inflammatory activity, 23 anesthetic activity, 4,24 as antiviral drugs, 6 anti-leukemic agents, 25 antiproliferatives (cytostatic and cytotoxic) with activity against a panel of cell lines (HeLa, L929, HT-29 and T47D), 26 as active agents against some enzymes involved in eicosanoid metabolism (5-, 12-, 15-lipoxygenase (LO), cyclooxygenase-1 and -2 (COX-1 and COX-2)), 27 inhibitors anti-TCR antibody induced IL-2 production in mice in vivo and reduced lung inflammation in a mouse model of ovalbumin induced allergy/asthma, 28 inhibitors for Mycobacterium tuberculosis (Mtb, H37Rv and MS, GyrB), 29,30 as vascular adhesion protein-1 inhibitors (VAP-1), 31,32 inhibitors of Cdc7 kinase activity in cancer cells, 33 inhibitors of nerve growth factor receptor TrkA, 34 inhibitors of p38α mitogen-activated protein kinase (p38α MAPK). 35 They can also bind to CT-DNA by the intercalative and electrostatic binding mode.…”

Section: Introductionmentioning

confidence: 99%

Recent Developments and Biological Activities of 2-Aminothiazole Derivatives

Khalifa

2018

ACSi

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Aminothiazole nuclei and their various derivatives have been long used as precursors for the synthesis of biologically active molecules. As a typical heterocyclic amine, 2-aminothiazole is a cornerstone for the synthesis of many compounds, including sulfur drugs, biocides, fungicides, various types of dyes for synthetic fibers and chemical reaction accelerators and as intermediates in the synthesis of antibiotics, where a large number of 2-aminothiazoles have been substituted with different groups for various pharmaceutical purposes, besides their activity as corrosion inhibitors for mild steel protection as well. The synthetic utility of 2-amino-4-substituted-thiazoles, their reactions and biological activities have been surveyed and are presented in this review.

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Synthesis and SAR study of new thiazole derivatives as vascular adhesion protein-1 (VAP-1) inhibitors for the treatment of diabetic macular edema

Cited by 16 publications

References 21 publications

PET ligands [ ¹⁸ F]LSN3316612 and [ ¹¹ C]LSN3316612 quantify O -linked-β- N -acetyl-glucosamine hydrolase in the brain

PET ligands [ ¹⁸ F]LSN3316612 and [ ¹¹ C]LSN3316612 quantify O -linked-β- N -acetyl-glucosamine hydrolase in the brain

Human Copper-Containing Amine Oxidases in Drug Design and Development

Recent Developments and Biological Activities of 2-Aminothiazole Derivatives

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Synthesis and SAR study of new thiazole derivatives as vascular adhesion protein-1 (VAP-1) inhibitors for the treatment of diabetic macular edema

Cited by 16 publications

References 21 publications

PET ligands [ 18 F]LSN3316612 and [ 11 C]LSN3316612 quantify O -linked-β- N -acetyl-glucosamine hydrolase in the brain

PET ligands [ 18 F]LSN3316612 and [ 11 C]LSN3316612 quantify O -linked-β- N -acetyl-glucosamine hydrolase in the brain

Human Copper-Containing Amine Oxidases in Drug Design and Development

Recent Developments and Biological Activities of 2-Aminothiazole Derivatives

Contact Info

Product

Resources

About

PET ligands [ ¹⁸ F]LSN3316612 and [ ¹¹ C]LSN3316612 quantify O -linked-β- N -acetyl-glucosamine hydrolase in the brain

PET ligands [ ¹⁸ F]LSN3316612 and [ ¹¹ C]LSN3316612 quantify O -linked-β- N -acetyl-glucosamine hydrolase in the brain