title: The synthesis of three 4-substituted benzo[b]thiophene-2-carboxamidines as potent and selective inhibitors of urokinase.
abstract: Efficient synthesis of structurally novel 4-substituted benzo[b]thiophene-2-carboxamidines 1-3, which selectively inhibit urokinase-type plasminogen activator (uPA) with IC50 values of 70-320 nM, are described. The key intermediate, methyl 4-iodobenzo[b]thiophene-2-carboxylate (7), is prepared from 3-fluoroiodobenzene in two steps in 70% overall yield via fluorine-directed metalation/formylation and subsequent thiophene annulation. Amidination of ester 7 gives the 320 nM inhibitor 1. Palladium-catalyzed arylacetylene and vinyl stannane couplings with ester 7 or 4-iodobenzo[b]thiophene-2-carbonitrile (16, derived from 7), respectively, followed by amidination leads to the more potent inhibitors 2 (IC50 = 133 nM) and 3 (IC50 = 70 nM). These compounds represent an important new class of synthetic uPA inhibitors, with carboxamidine 3 being the most potent selective inhibitor currently described in the literature.
authors.affiliation: Section of Chemistry, Eisai Research Institute, Andover, MA 01810.
authors.forename: A J
authors.initials: AJ
authors.lastname: Bridges
authors.forename: A
authors.initials: A
authors.lastname: Lee
authors.forename: C E
authors.initials: CE
authors.lastname: Schwartz
authors.forename: M J
authors.initials: MJ
authors.lastname: Towle
authors.forename: B A
authors.initials: BA
authors.lastname: Littlefield
mesh_terms: D000578:Amidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000584:Amiloride / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors*
chemical_list: D000578:Amidines; D013876:Thiophenes; D000584:Amiloride; D014568:Urokinase-Type Plasminogen Activator