title: SSR182289A, a selective and potent orally active thrombin inhibitor.
abstract: SSR182289A 1 is the result of a rational optimisation process leading to an orally active thrombin inhibitor. The structure incorporates an original 2-(acetylamino)-[1,1'-biphenyl]-3-sulfonyl N-terminal motif, a central l-Arg surrogate carrying a weakly basic 3-amino-pyridine, and an unusual 4-difluoropiperidine at the C-terminus. Its synthesis is convergent and palladium catalysis has been employed for the construction of the key C-C bonds: Suzuki coupling for the bis-aryl fragment and Sonogashira reaction for the delta- bond of the central amino-acid chain. The compound is a potent inhibitor of thrombin's activities in vitro and demonstrates potent oral anti-thrombotic potencies in three rat models of thrombosis. The observed in vitro potency could be rationalized through the examination of the interactions within the SSR182289A 1 - thrombin crystal structure. SSR182289A 1, has been therefore selected for further development.
authors.affiliation: Sanofi-Synthélabo Research, Cardiovascular-Thrombosis Department, 1 Avenue Pierre Brossolette, 91385 Chilly-Mazarin, Cedex, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Altenburger
authors.forename: Gilbert Y
authors.initials: GY
authors.lastname: Lassalle
authors.forename: Mostapha
authors.initials: M
authors.lastname: Matrougui
authors.forename: Daniel
authors.initials: D
authors.lastname: Galtier
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Jetha
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Bocskei
authors.forename: Christopher N
authors.initials: CN
authors.lastname: Berry
authors.forename: Catherine
authors.initials: C
authors.lastname: Lunven
authors.forename: Janine
authors.initials: J
authors.lastname: Lorrain
authors.forename: Jean-Pascal
authors.initials: JP
authors.lastname: Herault
authors.forename: Paul
authors.initials: P
authors.lastname: Schaeffer
authors.forename: Stephen E
authors.initials: SE
authors.lastname: O'Connor
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Herbert
mesh_terms: D000284:Administration, Oral; D000631:Aminopyridines / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D001384:Azetidines / Q000494:pharmacology; D001596:Benzylamines; D001777:Blood Coagulation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D006801:Humans; D006860:Hydrogen Bonding; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D010974:Platelet Aggregation / Q000187:drug effects; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000494:pharmacology*; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000502:physiology; D013927:Thrombosis / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control
chemical_list: D000631:Aminopyridines; D001384:Azetidines; D001596:Benzylamines; C469682:N-(3-((((4-(5-amino-2-pyridinyl)-1-((4-difluoromethylene)-1-piperidinyl)carbonyl)butyl)amino)sulfonyl)(1,1'-biphenyl)-2-yl) acetamide; D013449:Sulfonamides; C426686:ximelagatran; D013917:Thrombin