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

Abstract

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.

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

“…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).…”

Structure–activity relationships of the plasminogen modulator SMTP with respect to the inhibition of soluble epoxide hydrolase

“…26 A preliminary investigation has revealed that the selectivity of the inhibition of the two sEH activities greatly changed depending on the N-linked side-chain structure, demonstrating that SMTP binds to two distinct sites in sEH. 26 In conjunction with that the N-linked side chain is a crucial determinant for plasminogen modulation activity of SMTP, [10][11][12]14 it is possible that changing the N-linked side-chain structure leads to the generation of an SMTP congener specific or universal for each of the three targets, plasminogen, Cterm-EH and Nterm-phos. In this study, we tested a variety of SMTP congeners (25 including 6 new congeners) for their activities in inhibitions of sEH Cterm-EH and Nterm-phos in comparison with plasminogen modulation to understand structure-activity relationships that span the three targets.…”

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

“…Another possibility is the involvement of the anti‐inflammatory and anti‐oxidative actions of SMTP‐7 . Inflammatory and oxidative reactions play crucial roles in the development of ischemia‐reperfusion injury .…”

“…Another possibility is the involvement of the anti-inflammatory and anti-oxidative actions of SMTP-7. 11,19,39,40 Inflammatory and oxidative reactions play crucial roles in the development of ischemiareperfusion injury. 41 Indeed, there are several correlation networks that tie stroke pathologies with inflammatory responses in the embolic stroke model used in this study ( Figure 5A), suggesting a role of inflammation in stroke development in this model.…”