Substituted 3-(Phenylsulfonyl)-1-phenylimidazolidine-2,4-dione Derivatives as Novel Nonpeptide Inhibitors of Human Heart Chymase

Niwata, Shinjiro; Fukami, Hironobu; Sumida, Motoo; Ito, Akiko; Kakutani, Saki; Saitoh, Masayuki; Suzuki, Kenji; Imoto, Masahiro; Shibata, Hiroshi; Imajo, Seiichi; Kiso, Yoshinobu; Tanaka, Takaharu; Nakazato, Hiroshi; Ishihara, Takafumi; Yamamoto, Daisuke; Shiota, Naotaka; Miyazaki, Mizuo; Okunishi, Hideki; Kinoshita, Akio; Urata, Hidenori; Arakawa, Kikuo

doi:10.1021/jm960793t

Cited by 29 publications

(23 citation statements)

References 20 publications

(46 reference statements)

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“…6 One compound tested in this series sulfonyl]-1-(3,4-dimethylphenyl)imidazoline-2,4-dione; compound #41) is a potent chymase inhibitor showing no inhibition of the other major serine proteases chymotrypsin and cathepsin G. Thus, using the selective chymase inhibitor C41 and the selective chymase substrate [Pro, 11 D-Ala 12 ] Ang I (ProAng I), we assessed the functional role of chymase in the formation of Ang II in isolated human mammary arteries (IMAs). 3,[7][8][9] …”

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confidence: 99%

Functional Evidence for a Role of Vascular Chymase in the Production of Angiotensin II in Isolated Human Arteries

et al. 2001

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Background-In human arteries, angiotensin-converting enzyme (ACE) inhibitors incompletely block the production of angiotensin (Ang) II from Ang I. This ACE-independent production of Ang II appears to be caused by serine proteases, one of which presumably is chymase. However, several serine proteases may produce Ang II, and the exact role of chymase in the vascular production of Ang II has never been directly evaluated using selective chymase inhibitors. Methods and Results-Rings of human mammary arteries were subjected to either Ang I or the chymase-selective substrate [pro, ] Ang I in the absence or the presence of the ACE inhibitor captopril, the serine protease inhibitor chymostatin, or the selective chymase inhibitor C41. Captopril only partially inhibited (by 33%) the response to Ang I. In the absence of captopril, C41 markedly reduced (by 44%) the response to Ang I, and this effect was identical to that of chymostatin. C41 also significantly reduced the response to Ang I in the presence of captopril, although this inhibitory effect was slightly less than that of captopril in combination with chymostatin. [Pro, ] Ang I induced potent contractions that were not affected by captopril but were abolished by chymostatin and markedly reduced by C41. In addition, we found that prior treatment of the patients with an ACE inhibitor did not affect the in vitro response to Ang I (in the absence or the presence of captopril) or to [Pro, ] Ang I. Conclusions-Our results reinforce the hypothesis that chymase is a major serine protease implicated in the ACEindependent production of Ang II in human arteries. Key Words: angiotensin Ⅲ arteries Ⅲ vasoconstriction I n isolated human arteries, the production of angiotensin (Ang) II from Ang I is only partially blocked by Ang I-converting enzyme (ACE) inhibitors. These ACEindependent responses are blocked by inhibitors of serine proteases, 1-3 suggesting that they are mediated by one or more serine proteases, presumably including chymase. 4 However, many serine proteases other than chymase have been shown to produce Ang II from Ang I, 5 and the exact functional role of chymase has never been demonstrated directly because of the lack of chymase inhibitors that do not also inhibit other serine proteases.Recently, a series of nonpeptide inhibitors of human heart chymase has been described. 6 One compound tested in this series (3-[(3,4-Dimethoxyphenyl)sulfonyl]-1-(3,4-dimethylphenyl)imidazoline-2,4-dione; compound #41) is a potent chymase inhibitor showing no inhibition of the other major serine proteases chymotrypsin and cathepsin G. Thus, using the selective chymase inhibitor C41 and the selective chymase substrate [Pro, 11 D-Ala 12 ] Ang I (ProAng I), we assessed the functional role of chymase in the formation of Ang II in isolated human mammary arteries (IMAs). 3,7-9 MethodsDistal segments of the IMA, not used for surgical implantation, were obtained from 70 patients and mounted in organ chambers. All handling of human tissue was performed in such a manner as to avoid possible c...

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Functional Evidence for a Role of Vascular Chymase in the Production of Angiotensin II in Isolated Human Arteries

et al. 2001

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“…On the other hand, in the case of nonpeptide human chymase inhibitors, Niwata et al (26) suggested that 3-(phenylsulfonyl)-1-phenylimidazolidine-2,4-dione derivatives could form hydrogen bonds with the anion hole and the side chain of His45 and could interact with the P1 hole, Arg130 and Lys179. In accordance with the report of Eda et al (25) and Aoyama et al (27) also reported that 1-oxacephem-based inhibitors formed hydrogen bonds with Gly180 and Ser182 and electrostatically interacted with Lys28.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory Mechanism of Daphnodorins for Human Chymase

Sakaguchi

Yamamoto

Jin

et al. 2001

Biochemical and Biophysical Research Communications

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“…In the search for new ligands targeting the chymase enzyme, we initiated a focussed library synthesis based on the hydantoin skeleton. Niwata et al 10 have described 3-(phenylsulfonyl)-1-phenylimidazolidine-2,4-diones 1 with interesting activities and we have recently described the synthesis of active 1,5-dibenzyl-3-(arylsulfonyl) imidazolidine-2,4-diones 2. 11 Consequently we decided to synthesize three different families of compounds which possess a strained conformation as potential chymase inhibitors 3, 4 and 5 (Scheme 1).…”

Section: Introductionmentioning

confidence: 89%

Design and Synthesis of Indole and Tetrahydroisoquinoline Hydantoin Derivatives as Human Chymase Inhibitors

Alagille

Pfeiffer

Scalbert

et al. 2004

Journal of Enzyme Inhibition and Medicinal Chemistry

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Substituted 3-(Phenylsulfonyl)-1-phenylimidazolidine-2,4-dione Derivatives as Novel Nonpeptide Inhibitors of Human Heart Chymase

Cited by 29 publications

References 20 publications

Functional Evidence for a Role of Vascular Chymase in the Production of Angiotensin II in Isolated Human Arteries

Functional Evidence for a Role of Vascular Chymase in the Production of Angiotensin II in Isolated Human Arteries

Inhibitory Mechanism of Daphnodorins for Human Chymase

Design and Synthesis of Indole and Tetrahydroisoquinoline Hydantoin Derivatives as Human Chymase Inhibitors

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