title: Diamino benzo[b]thiophene derivatives as a novel class of active site directed thrombin inhibitors. 5. Potency, efficacy, and pharmacokinetic properties of modified C-3 side chain derivatives.
abstract: A systematic investigation of the structure-activity relationships of the C-3 side chain of the screening hit 1a led to the identification of the potent thrombin inhibitors 23c, 28c, and 31c. Their activities (1240, 903, and 1271 x 10(6) L/mol, respectively) represent 2200- and 2900-fold increases in potency over the starting lead 1a. This activity enhancement was accomplished with an increase of thrombin selectivity. The in vitro anticoagulant profiles of derivatives 28c and 31c were determined, and they compare favorably with the clinical agent H-R-1-[4aS, 8aS]perhydroisoquinolyl-prolyl-arginyl aldehyde (D-Piq-Pro-Arg-H; 32). The more potent members of this series have been studied in an arterial/venous shunt (AV shunt) model of thrombosis and were found to be efficacious in reducing clot formation. However, their efficacy is currently limited by their rapid and extensive distribution following administration.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Sall
authors.forename: D L
authors.initials: DL
authors.lastname: Bailey
authors.forename: J A
authors.initials: JA
authors.lastname: Bastian
authors.forename: J A
authors.initials: JA
authors.lastname: Buben
authors.forename: N Y
authors.initials: NY
authors.lastname: Chirgadze
authors.forename: A C
authors.initials: AC
authors.lastname: Clemens-Smith
authors.forename: M L
authors.initials: ML
authors.lastname: Denney
authors.forename: M J
authors.initials: MJ
authors.lastname: Fisher
authors.forename: D D
authors.initials: DD
authors.lastname: Giera
authors.forename: D S
authors.initials: DS
authors.lastname: Gifford-Moore
authors.forename: R W
authors.initials: RW
authors.lastname: Harper
authors.forename: L M
authors.initials: LM
authors.lastname: Johnson
authors.forename: V J
authors.initials: VJ
authors.lastname: Klimkowski
authors.forename: T J
authors.initials: TJ
authors.lastname: Kohn
authors.forename: H S
authors.initials: HS
authors.lastname: Lin
authors.forename: J R
authors.initials: JR
authors.lastname: McCowan
authors.forename: A D
authors.initials: AD
authors.lastname: Palkowitz
authors.forename: M E
authors.initials: ME
authors.lastname: Richett
authors.forename: G F
authors.initials: GF
authors.lastname: Smith
authors.forename: D W
authors.initials: DW
authors.lastname: Snyder
authors.forename: K
authors.initials: K
authors.lastname: Takeuchi
authors.forename: J E
authors.initials: JE
authors.lastname: Toth
authors.forename: M
authors.initials: M
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D006801:Humans; D066298:In Vitro Techniques; D008958:Models, Molecular; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D013917:Thrombin / Q000037:antagonists & inhibitors*; D013927:Thrombosis / Q000097:blood / Q000378:metabolism
chemical_list: C405044:1-(2-((5-(6-hydroxy-3-((3-methoxy-4-((1-pyrrolidinyl)methyl)phenyl)methyl)benzo(b)thiophen-2-yl)pyrid-2-yl)oxy)ethyl)pyrrolidine; C405043:6-hydroxy-3-(3-methoxy-4-((1-pyrrolidinyl)methyl)benzyl)-2-(4-(2-(1-pyrrolidinyl)ethoxy)phenyl)benzo(b)thiophene; D000925:Anticoagulants; D011759:Pyrrolidines; D015842:Serine Proteinase Inhibitors; D013876:Thiophenes; D013917:Thrombin