Synthesis and SAR study of new thiazole derivatives as vascular adhesion protein-1 (VAP-1) inhibitors for the treatment of diabetic macular edema: Part 2

Inoue, Takayuki; Morita, Masataka; Tojo, Takashi; Nagashima, Akira; Moritomo, Ayako; Imai, Keisuke; Miyake, Hiroshi

doi:10.1016/j.bmc.2013.02.048

Cited by 14 publications

(14 citation statements)

References 18 publications

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“…The binding mode is also different from all recent computational studies, where docking and QSAR models of potential VAP-1 inhibitors have been published 19, 20, 30, 37–39 . Unlike 2HP, which binds covalently to TPQ 14 , the molecules 6 , 7 , and 13 bind non-covalently in the channel leading to the active site.…”

Section: Resultsmentioning

confidence: 60%

Novel Pyridazinone Inhibitors for Vascular Adhesion Protein-1 (VAP-1): Old Target–New Inhibition Mode

et al. 2013

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Vascular adhesion protein-1 (VAP-1) is a primary amine oxidase and a drug target for inflammatory and vascular diseases. Despite extensive attempts to develop potent, specific and reversible inhibitors of its enzyme activity, the task has proven challenging. Here we report the synthesis, inhibitory activity and molecular binding mode of novel pyridazinone inhibitors, which show specificity for VAP-1 over monoamine and diamine oxidases. The crystal structures of three inhibitor-VAP-1 complexes show that these compounds bind reversibly into a unique binding site in the active site channel. Though they are good inhibitors of human VAP-1, they do not inhibit rodent VAP-1 well. To investigate this further, we used homology modeling and structural comparison to identify amino acid differences, which explain the species-specific binding properties. Our results prove the potency and specificity of these new inhibitors and the detailed characterization of their binding mode is of importance for further development of VAP-1 inhibitors.

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Section: Resultsmentioning

confidence: 60%

Novel Pyridazinone Inhibitors for Vascular Adhesion Protein-1 (VAP-1): Old Target–New Inhibition Mode

et al. 2013

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“…Recombinant chemistry and high-throughput screening assays yield unprecedented numbers of drug candidates, while biomaterials selected for in vivo testing undergo less selection pressure than the drugs or compounds they deliver since efficacy is not a pre-test endpoint (Anderson, Putnam, Lavik, Mahmood, & Langer, 2005;Butler, Itotia, & Sullivan, 2010;Inoue et al, 2013;Langer & Tirrell, 2004;Zaneveld, Wang, Wang, & Chen, 2013). To overcome this challenge, we suggest that significant advantage would derive from the use of serial, non-invasive in vivo toxicity testing.…”

Section: Introductionmentioning

confidence: 97%

Fundus autofluorescence (FAF) non-invasively identifies chorioretinal toxicity in a rat model of retinal pigment epithelium (RPE) damage

Baek

Liang

Zhao

et al. 2015

Journal of Pharmacological and Toxicological Methods

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“…PXS-4728A (now known as BI 1467335) was purchased from Axon MedChem. Compound 35c was synthesized as described by Inoue et al [19] while LJP-1207 was synthesized as described by Salter-Cid et al [22].…”

Section: 2mentioning

confidence: 99%

“…Inhibition of the amine oxidase activity of VAP-1 has been shown to abrogate the recruitment of leukocytes, especially neutrophils, to sites of inflammation in vivo and the transendothelial migration of leukocytes in vitro [15,16]. These findings have led to medicinal chemistry efforts to inhibit VAP-1 deamination activity as an approach to anti-inflammation therapies [17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Comparison of Inhibitor and Substrate Selectivity between Rodent and Human Vascular Adhesion Protein-1

Kubota

Reid

Lieu

et al. 2020

Mediators of Inflammation

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Vascular adhesion protein-1 (VAP-1) is an ectoenzyme that functions as a copper-containing amine oxidase and is involved in leukocyte adhesion at sites of inflammation. Inhibition of VAP-1 oxidative deamination has become an attractive target for anti-inflammatory therapy with demonstrated efficacy in rodent models of inflammation. A previous comparison of purified recombinant VAP-1 from mouse, rat, monkey, and human gene sequences predicted that rodent VAP-1 would have higher affinity for smaller hydrophilic substrates/inhibitors because of its narrower and more hydrophilic active site channel. An optimized in vitro oxidative deamination fluorescence assay with benzylamine (BA) was used to compare inhibition of five known inhibitors in recombinant mouse, rat, and human VAP-1. Human VAP-1 was more sensitive compared to rat or mouse VAP-1 (lowest IC50 concentration) to semicarbazide but was least sensitive to hydralazine and LJP-1207. Hydralazine had a lower IC50 in rats compared to humans, although not significant. However, the IC50 of hydralazine was significantly higher in the rat compared to mouse VAP-1. The larger hydrophobic compounds from Astellas (compound 35c) and Boehringer Ingelheim (PXS-4728A) were hypothesized to have higher binding affinity for human VAP-1 compared to rodent VAP-1 since the channel in human VAP-1 is larger and more hydrophobic than that in rodent VAP-1. Although the sensitivity of these two inhibitors was the lowest in the mouse enzyme, we found no significant differences between mouse, rat, and human VAP-1. Michaelis-Menten kinetics of the small primary amines phenylethylamine and tyramine were also compared to the common marker substrate BA demonstrating that BA had the highest affinity among the substrates. Rat VAP-1 had the highest affinity for all three substrates and mouse VAP-1 had intermediate affinity for BA and phenylethylamine, but tyramine was not a substrate for mouse VAP-1 under these assay conditions. These results suggest that comparing oxidative deamination in mouse and rat VAP-1 may be important if using these species for preclinical efficacy models.

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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: Part 2

Cited by 14 publications

References 18 publications

Novel Pyridazinone Inhibitors for Vascular Adhesion Protein-1 (VAP-1): Old Target–New Inhibition Mode

Novel Pyridazinone Inhibitors for Vascular Adhesion Protein-1 (VAP-1): Old Target–New Inhibition Mode

Fundus autofluorescence (FAF) non-invasively identifies chorioretinal toxicity in a rat model of retinal pigment epithelium (RPE) damage

Comparison of Inhibitor and Substrate Selectivity between Rodent and Human Vascular Adhesion Protein-1

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