title: 2-Amidino analogs of glycine-amiloride conjugates: inhibitors of urokinase-type plasminogen activator.
abstract: The relative non-toxicity of the diuretic amiloride, coupled with its selective inhibition of the protease urokinase plasminogen activator (uPA), makes this compound class attractive for structure-activity studies. Herein we substituted the C(2)-acylguanidine of C(5)-glycyl-amiloride with amidine and amidoxime groups. The data show the importance of maintaining C(5)-hydrophobicity. The C(5)-benzylglycine analogs containing either C(2)-acylguanidine or amidine inhibited uPA with an IC(50) ranging from 3 to 7 μM and were cytotoxic to human U87 malignant glioma cells.
authors.affiliation: Department of Chemistry, University of Louisville, Louisville, KY 40292, USA.
authors.forename: Archna P
authors.initials: AP
authors.lastname: Massey
authors.forename: William R
authors.initials: WR
authors.lastname: Harley
authors.forename: NagaRekha
authors.initials: N
authors.lastname: Pasupuleti
authors.forename: Fredric A
authors.initials: FA
authors.lastname: Gorin
authors.forename: Michael H
authors.initials: MH
authors.lastname: Nantz
mesh_terms: D000578:Amidines / Q000138:chemical synthesis* / Q000494:pharmacology; D000584:Amiloride / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005998:Glycine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D010959:Tissue Plasminogen Activator / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000578:Amidines; D000970:Antineoplastic Agents; D015842:Serine Proteinase Inhibitors; D000584:Amiloride; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator; D005998:Glycine