title: Amidinohydrazones as guanidine bioisosteres: application to a new class of potent, selective and orally bioavailable, non-amide-based small-molecule thrombin inhibitors.
abstract: We describe a new class of potent, non-amide-based small molecule thrombin inhibitors in which an amidinohydrazone is used as a guanidine bioisostere on a non-peptide scaffold. Compound 4 exhibits nM inhibition of thrombin, is selective for thrombin, and shows 60 and 23% bioavailability in rabbits and dogs, respectively. Crystallographic analysis of 4 bound to thrombin confirmed the amindinohydrazone binding mode.
authors.affiliation: 3-Dimensional Pharmaceuticals, Eagleview Corporate Center, Exton, PA 19341, USA. soll@3dp.com
authors.forename: R M
authors.initials: RM
authors.lastname: Soll
authors.forename: T
authors.initials: T
authors.lastname: Lu
authors.forename: B
authors.initials: B
authors.lastname: Tomczuk
authors.forename: C R
authors.initials: CR
authors.lastname: Illig
authors.forename: C
authors.initials: C
authors.lastname: Fedde
authors.forename: S
authors.initials: S
authors.lastname: Eisennagel
authors.forename: R
authors.initials: R
authors.lastname: Bone
authors.forename: L
authors.initials: L
authors.lastname: Murphy
authors.forename: J
authors.initials: J
authors.lastname: Spurlino
authors.forename: F R
authors.initials: FR
authors.lastname: Salemme
mesh_terms: D000284:Administration, Oral; D000578:Amidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D001682:Biological Availability; D018360:Crystallography, X-Ray; D004285:Dogs; D005343:Fibrinolytic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006146:Guanidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D007700:Kinetics; D011817:Rabbits; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013917:Thrombin / Q000037:antagonists & inhibitors*; D014361:Trypsin Inhibitors / Q000494:pharmacology
chemical_list: D000578:Amidines; D005343:Fibrinolytic Agents; D006146:Guanidines; D015842:Serine Proteinase Inhibitors; D014361:Trypsin Inhibitors; D013917:Thrombin