title: Design and synthesis of 4,5-disubstituted-thiophene-2-amidines as potent urokinase inhibitors.
abstract: A study of the S1 binding of lead 5-methylthiothiophene amidine 3, an inhibitor of urokinase-type plasminogen activator, was undertaken by the introduction of a variety of substituents at the thiophene 5-position. The 5-alkyl substituted and unsubstituted thiophenes were prepared using organolithium chemistry. Heteroatom substituents were introduced at the 5-position using a novel displacement reaction of 5-methylsulfonylthiophenes and the corresponding oxygen or sulfur anions. Small alkyl group substitution at the 5-position provided inhibitors equipotent with but possessing improved solubility.
authors.affiliation: 3-Dimensional Pharmaceuticals Inc., 665 Stockton Drive, Exton, PA 19341, USA. rudolph@3dp.com
authors.forename: M Jonathan
authors.initials: MJ
authors.lastname: Rudolph
authors.forename: Carl R
authors.initials: CR
authors.lastname: Illig
authors.forename: Nalin L
authors.initials: NL
authors.lastname: Subasinghe
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Wilson
authors.forename: James B
authors.initials: JB
authors.lastname: Hoffman
authors.forename: Troy
authors.initials: T
authors.lastname: Randle
authors.forename: David
authors.initials: D
authors.lastname: Green
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Molloy
authors.forename: Richard M
authors.initials: RM
authors.lastname: Soll
authors.forename: Frank
authors.initials: F
authors.lastname: Lewandowski
authors.forename: Marie
authors.initials: M
authors.lastname: Zhang
authors.forename: Roger
authors.initials: R
authors.lastname: Bone
authors.forename: John C
authors.initials: JC
authors.lastname: Spurlino
authors.forename: Ingrid C
authors.initials: IC
authors.lastname: Deckman
authors.forename: Carl
authors.initials: C
authors.lastname: Manthey
authors.forename: Celia
authors.initials: C
authors.lastname: Sharp
authors.forename: Diane
authors.initials: D
authors.lastname: Maguire
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Grasberger
authors.forename: Renée L
authors.initials: RL
authors.lastname: DesJarlais
authors.forename: Zhao
authors.initials: Z
authors.lastname: Zhou
mesh_terms: D000478:Alkylation; D000578:Amidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D007202:Indicators and Reagents; D018020:Lithium Compounds / Q000737:chemistry; D011485:Protein Binding; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000494:pharmacology; D013876:Thiophenes / Q000138:chemical synthesis* / Q000494:pharmacology*; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors*
chemical_list: D000578:Amidines; D007202:Indicators and Reagents; D018020:Lithium Compounds; D015842:Serine Proteinase Inhibitors; D013844:Thiazoles; D013876:Thiophenes; D014568:Urokinase-Type Plasminogen Activator