title: Structure-activity relationships of the plasminogen modulator SMTP with respect to the inhibition of soluble epoxide hydrolase.
abstract: A family of fungal metabolites, SMTP, is a small-molecule plasminogen modulator that enhances plasminogen activation, leading to thrombolysis. We recently demonstrated that SMTP-7 effectively treats ischemic stroke due to its thrombolytic activity as well as anti-inflammatory action, which is attributable to soluble epoxide hydrolase (sEH) inhibition. In this paper, we studied detailed structure-activity relationships of plasminogen modulation and sEH inhibition using 25 SMTP congeners including six newly synthesized ones. The results clearly demonstrate that the structure of the N-linked side chain of SMTP congeners markedly affect their activities toward plasminogen modulation and inhibitions of the two activities of sEH (C-terminal epoxide hydrolase and N-terminal phosphatase). A slight change in the N-linked side chain results in affording selectivity of SMTP congeners. Many congeners, which lacked plasminogen modulation activity, differently inhibited the two sEH activities depending on the structures of the N-linked side chain. Some congeners were active in plasminogen modulation and inhibition of both activities of sEH. These results help comprehensive understanding of ideal design of a drug useful for ischemic diseases that are associated with inflammation, such as stroke.
authors.affiliation: Department of Applied Biological Science, Tokyo Noko University, Tokyo, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Matsumoto
authors.affiliation: Department of Applied Biological Science, Tokyo Noko University, Tokyo, Japan.
authors.forename: Eriko
authors.initials: E
authors.lastname: Suzuki
authors.affiliation: Department of Applied Biological Science, Tokyo Noko University, Tokyo, Japan.
authors.forename: Kota
authors.initials: K
authors.lastname: Tsujihara
authors.affiliation: Department of Applied Biological Science, Tokyo Noko University, Tokyo, Japan.
authors.forename: Yuuichi
authors.initials: Y
authors.lastname: Nishimura
authors.affiliation: Department of Applied Biological Science, Tokyo Noko University, Tokyo, Japan.|Division of Research and Development, TMS Co., Ltd, Tokyo, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Hasumi
mesh_terms: D001578:Benzopyrans / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D010636:Phenols / Q000494:pharmacology*; D010960:Plasminogen Activators / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000494:pharmacology*; D013191:Stachybotrys / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D001578:Benzopyrans; D010636:Phenols; D011760:Pyrrolidinones; C409191:SMTP 7; D004851:Epoxide Hydrolases; D010960:Plasminogen Activators