A new series of the SMTP plasminogen modulator with a phenylglycine-based side chain

Koide, Haruki; Narasaki, Ritsuko; Hasegawa, Keiko; Nishimura, Naoko; Hasumi, Keiji

doi:10.1038/ja.2011.108

Cited by 19 publications

(29 citation statements)

References 19 publications

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“…SMTP Congeners-The SMTP congeners used in this study were produced by S. microspora as described previously (11)(12)(13)(31)(32)(33)(34). For in vivo studies, SMTP-7 and SMTP-44D were converted to respective sodium salts.…”

Section: Methodsmentioning

confidence: 99%

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Soluble Epoxide Hydrolase as an Anti-inflammatory Target of the Thrombolytic Stroke Drug SMTP-7

Matsumoto

Suzuki

Ishikawa

et al. 2014

Journal of Biological Chemistry

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Background:The small molecule thrombolytic SMTP-7 excels in the treatment of ischemic stroke through an unidentified anti-inflammatory activity. Results: Affinity purification and inhibition studies reveal that SMTP-7 and its congeners inhibit soluble epoxide hydrolase (sEH), an enzyme responsible for inflammation. Conclusion: sEH is the plausible in vivo anti-inflammatory target of SMTP-7. Significance: Dual-targeting of thrombolysis and sEH is a promising strategy for novel stroke therapy.

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Section: Methodsmentioning

confidence: 99%

“…3, A and B). Thus, the structural requirement for sEH inhibition is clearly distinguishable from that for plasminogen modulation activity in which the N-linked side chain plays a crucial role (11,12,32).…”

Section: Tablementioning

confidence: 99%

Soluble Epoxide Hydrolase as an Anti-inflammatory Target of the Thrombolytic Stroke Drug SMTP-7

Matsumoto

Suzuki

Ishikawa

et al. 2014

Journal of Biological Chemistry

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“…Previous studies have identified 31 SMTP congeners, most of which differ in the N-linked side chain. [13][14][15][16][17][18][19][20] The N-linked side chain structure of SMTP affects the plasminogen-modulating activity of the congeners. It has been suggested that a negatively ionizable group in the side chain is crucial for activity.…”

Section: Introductionmentioning

confidence: 99%

“…19 Investigations of the congeners with a phenylglycine-based side chain suggest that a phenolic hydroxy group in the side chain affects potency of a congener. 20 In this study, we isolated 11 new SMTP congeners with a phenylamine-based side chain and investigated the roles for a side chain-phenolic hydroxy group and a carboxylic acid group in the plasminogen-modulating activity. This paper deals with the isolation and characterization of these congeners.…”

Section: Introductionmentioning

confidence: 99%

“…25-522.25. A phenolic hydroxy group reduces the activity of a congener with a phenylglycine-based side chain, 20 but has differential effects in activity in combination with a carboxylic acid group. For example, with respect to the congeners with 28-COOH, the presence of 27-OH (SMTP-25) greatly increases activity compared with the congener with 28-COOH but without a hydroxy group .…”

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A new series of the SMTP plasminogen modulators with a phenylamine-based side chain

Koide

Hasegawa²,

Nishimura³

et al. 2012

J Antibiot

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SMTPs are a family of small-molecule plasminogen modulators that enhance plasminogen activation. SMTP-7, one of the most potent congeners, is effective in treating thrombotic cerebral infarction. The SMTP molecule consists of a tricyclic c-lactam moiety, a geranylmethyl group, and an N-linked side chain. The presence of both an aromatic group and a negatively ionizable group in the N-linked side chain is crucial for activity. Investigations of the congeners with a phenylglycine-based side chain suggest that a phenolic hydroxy group affects potency. In this study, we isolate and characterize a series of novel SMTP congeners with a phenylamine-based N-linked side chain. Of the 11 congeners isolated, SMTP-19 (with a 4-phenylcarboxylic acid moiety), SMTP-22 (with a 3-hydroxyphenyl-4-carboxylic acid moiety) and SMTP-25 (with a 2-hydroxyphenyl-3-carboxylic acid moiety) are as potent as SMTP-7 in plasminogen-modulating activity. Their isomers with a carboxylic acid group and/or a phenolic hydroxy group at different positions have o40% of the activity of these congeners. Both SMTP-22 and SMTP-25 have 41.7 times more oxygen radical absorbance capacity as compared with SMTP-7.

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Efficacy of SMTP‐7, a small‐molecule anti‐inflammatory thrombolytic, in embolic stroke in monkeys

Suzuki

Nishimura²,

Yoshikawa

et al. 2018

Pharmacology Res & Perspec

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SMTP‐7 (Stachybotrys microspora triprenyl phenol‐7) is a small molecule that promotes thrombolysis and suppresses inflammation possibly through plasminogen modulation and soluble epoxide hydrolase (sEH) inhibition, respectively. Here, we demonstrate an efficacy of SMTP‐7 in a severe embolic stroke model in monkeys. The middle cerebral artery was embolized by an autologous blood clot. Saline, SMTP‐7, or tissue‐type plasminogen activator (t‐PA) (n = 5 in each group) was given after 3 hours, and neurologic deficit scoring and infarct characterization were performed after 24 hours. Hemorrhagic infarct‐accompanied premature death was observed for two animals in t‐PA group. SMTP‐7 treatment significantly reduced the sizes of infarct by 65%, edema by 37%, and clot by 55% compared to saline treatment. Plasma levels of the products of plasminogen activation (plasmin‐α2‐antiplasmin complex) and sEH reaction (dihydroxyeicosatrienoic acid) in SMTP‐7 group were 794% (P < 0.05) and 60% (P = 0.085) compared to saline group, respectively. No significant changes in the plasma levels of MMP‐9, CRP, MCP‐1, and S100B were found. There was an inverse correlation between plasmin‐α2‐antiplasmin complex level and infarct volume (r = 0.93, P < 0.05), suggesting a role of thrombolysis in the SMTP‐7 action to limit infarct development. In conclusion, SMTP‐7 is effective in treating severe embolic stroke in monkeys under conditions where t‐PA treatment tends to cause hemorrhagic infarct‐associated premature death.

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A new series of the SMTP plasminogen modulator with a phenylglycine-based side chain

Cited by 19 publications

References 19 publications

Soluble Epoxide Hydrolase as an Anti-inflammatory Target of the Thrombolytic Stroke Drug SMTP-7

Soluble Epoxide Hydrolase as an Anti-inflammatory Target of the Thrombolytic Stroke Drug SMTP-7

A new series of the SMTP plasminogen modulators with a phenylamine-based side chain

Efficacy of SMTP‐7, a small‐molecule anti‐inflammatory thrombolytic, in embolic stroke in monkeys

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