Effects of a Novel PAF Antagonist, E6123, on PAF-Induced Biological Responses

Tsunoda, Hajime; Sakuma, Y.; Harada, Koukichi; Muramoto, Koji; Katayama, Satoshi; Horie, Tetsuhiro; Shimomura, Naoyuki; Clark, Richard D.; Miyazawa, Shuhei; Okano, Kōji

doi:10.1007/978-3-0348-7379-6_34

Cited by 3 publications

(3 citation statements)

References 4 publications

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“…There is another phosphodiesterase inhibitor, denbufylline (Figure (6)), which has the function xviii. Talampanel (Figure (7)), 3 (E-6123; Figure (8)), , and resiquimod (Figure (9)) also share similar substructures with midazolam. They have the functions xix, viii, and xiii, respectively.…”

Section: Resultsmentioning

confidence: 93%

In Silico Functional Profiling of Small Molecules and Its Applications

et al. 2008

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In silico screening is routinely used in the drug discovery process to predict whether each molecule in a database has a function of interest, such as inhibitory activity for a target protein. However, drugs generally have multiple functions including adverse effects. In order to obtain small molecules with desirable physiological effects, it is useful to simultaneously predict as many functions as possible. We employed Support Vector Machine to build classification models for 125 molecular functions, derived from the MDDR database, which showed higher kappa statistics (0.775 on average) than those of predictions by Tanimoto similarity (0.708). By analyzing the patterns of the predicted values (functional profiles) of 871 marketed drugs, we demonstrated its applications to indication discovery, clustering of drugs, and detection of molecular actions related to adverse effects. The results showed that functional profiling can be a useful tool for identifying the multifunctionality or adverse effects of small molecules.

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Section: Resultsmentioning

confidence: 93%

In Silico Functional Profiling of Small Molecules and Its Applications

et al. 2008

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“… 16,17 Some PAF antagonists, including Y‐24180 are now undergoing clinical trials. 18 Y‐24180 has been demonstrated to be a potent and long‐acting PAF antagonist with a high affinity for the PAF receptor 1 and able to reduce PAF‐induced airway hyperresponsiveness 19 and allergen‐induced airway resistance following oral administration in guinea pigs. 2,20 In addition, Y‐24180 has been reported to significantly improve the provocative concentration‐forced expiratory volume (PC 20 ‐FEV 1 ) value of asthmatic patients.…”

Section: Discussionmentioning

confidence: 99%

Possibility of lipid microsphere-encapsulated Y-24180 as an injectable drug and an inhaler for the treatment of bronchoconstriction

Takenaga

Igarashi

Mizushima

2000

Allergology International

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Y‐24180 ((±)‐4‐(2‐chloro‐phenyl)‐2‐[2‐(4‐isobuthylphenyl)ethyl]‐6,9‐dimethyl‐6H‐thieno[3,2f][1,2,4]triazolo[4,3‐a)[1,4]diazepine) is a lipophilic platelet‐ activating factor (PAF) antagonist. In the present study, we incorporated Y‐24180 into lipid microspheres (LM) and its activity was evaluated in vivo. When Lipo Y‐24180 was intravenously given 3 min before PAF injection, the maximal bronchoconstriction was reduced. The mean (±SEM) PAF‐induced respiratory flow resistance in Lipo Y‐24180 (1 μg/kg)‐treated animals at 0.5 min was 19.0 ± 8.0%, which was significantly lower than that of the vehicle‐treated control (61.5 ± 13.0%; P < 0.05). Three and 10 μg/kg Lipo Y‐24180 almost completely inhibited the respiratory flow resistance. Alone, Y‐24180 dose‐dependently suppressed the bronchoconstriction; however, a significant decrease was only seen in 10 μg/kg‐treated animals. There were also significant differences between the Lipo Y‐24180 (1 μg/kg)‐treated group and Y‐24180 (1 and 3 mg/kg) treated groups. Aerosol inhalation of Lipo Y‐24180 (10 μg/mL) caused no significant suppression; however, a significant inhibition was observed in guinea pigs that were administered more than 30 μg/mL. Therefore, it would be concluded that Lipo Y‐24180 would have a potency as a bronchodilator and would be promising as both an injectable drug and an inhaler.

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“…E 6123 (Eisai) is another potent hetrazepine PAF antagonist currently under development [5, 391. We have chosen to calculate the (S)-(+) isomer, known to be 50-200 times more potent than its enantiomer [40]. Again, we have found four low-lying conformers (A-D) within 1 kcal/mol.…”

Section: Paf Model Geometriesmentioning

confidence: 99%