title: Rational design, synthesis, and X-ray structure of selective noncovalent thrombin inhibitors.
abstract: We have designed, synthesized, and tested in vitro a novel class of noncovalent thrombin inhibitors. The main feature of these inhibitors is a 6,5-fused bicyclic core structure that fills the S2 pocket of the active site of thrombin. The bicycle introduces conformational constraint into the ligand and locks the Xaa-Pro amide bond into the desired trans configuration. Among the known ring systems, we selected by molecular modeling the 7-thiaindolizidinones (BTD) as our basic template. The influence of several structural features was analyzed: the length of the argininal side chain, the stereochemistry at C6, and the importance of making optimal use of the S3 pocket. Finally, an X-ray crystal structure of inhibitor 15 bound to thrombin was obtained at a resolution of 2.3 A. These designed thrombin inhibitors, which were prepared by an efficient synthesis, showed high selectivity over trypsin and other serine proteases. Further derivation based on the information obtained by X-ray crystallography should certainly allow to improve the potency.
authors.affiliation: Novartis Pharma AG, CH-4002 Basel, Switzerland.
authors.forename: J
authors.initials: J
authors.lastname: Wagner
authors.forename: J
authors.initials: J
authors.lastname: Kallen
authors.forename: C
authors.initials: C
authors.lastname: Ehrhardt
authors.forename: J P
authors.initials: JP
authors.lastname: Evenou
authors.forename: D
authors.initials: D
authors.lastname: Wagner
mesh_terms: D000818:Animals; D001665:Binding Sites; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002417:Cattle; D018360:Crystallography, X-Ray; D015195:Drug Design; D065427:Factor Xa Inhibitors; D006146:Guanidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013237:Stereoisomerism; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014361:Trypsin Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D065427:Factor Xa Inhibitors; D006146:Guanidines; D008024:Ligands; C114609:N-(3-((aminoiminomethyl)amino)propyl)-hexahydro-5-oxo-6-(((phenylmethyl)sulfonyl)amino)-5H-thiazolo(3,2-a)pyridine-3-carboxamide; D015842:Serine Proteinase Inhibitors; D013844:Thiazoles; D014361:Trypsin Inhibitors; D013917:Thrombin