title: Structure-activity relationships of new NAPAP-analogs.
abstract: Several new analogs of the known thrombin inhibitor NAPAP were synthesized, in which the P2 glycine residue was substituted by natural and unnatural amino acids. The thrombin inhibitory potency was comparable to that of NAPAP. Several of the compounds had inhibition constants lower than 10 nM and a very high selectivity compared to trypsin, factor Xa and plasmin. In addition, analogs were prepared by alkylation of the N(alpha)-atom of the 4-amidinophenylalanine in P1 position, which showed a more than 10-fold lower thrombin inhibition. Furthermore, azaglycine was introduced instead of P2 glycine. For most of the inhibitors similar fast elimination rates were seen in rats after intravenous dosing, as found previously for NAPAP. Only some compounds, which contained a second basic group showed a slightly decreased cumulative biliary clearance.
authors.affiliation: Inst. of Biochemistry & Biophysics, Friedrich Schiller University, Jena, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Steinmetzer
authors.forename: Andrea
authors.initials: A
authors.lastname: Schweinitz
authors.forename: Sebastian
authors.initials: S
authors.lastname: Künzel
authors.forename: Peter
authors.initials: P
authors.lastname: Wikström
authors.forename: Jörg
authors.initials: J
authors.lastname: Hauptmann
authors.forename: Jörg
authors.initials: J
authors.lastname: Stürzebecher
mesh_terms: D000991:Antithrombins / Q000737:chemistry* / Q000494:pharmacology; D004151:Dipeptides / Q000737:chemistry* / Q000494:pharmacology; D065427:Factor Xa Inhibitors; D005341:Fibrinolysin / Q000037:antagonists & inhibitors; D007700:Kinetics; D015394:Molecular Structure; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology; D011621:Pteridines / Q000737:chemistry* / Q000494:pharmacology; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship; D014361:Trypsin Inhibitors / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000991:Antithrombins; D004151:Dipeptides; D065427:Factor Xa Inhibitors; D010880:Piperidines; D011480:Protease Inhibitors; D011621:Pteridines; D014361:Trypsin Inhibitors; C038708:N(alpha)-(2-naphthylsulfonylglycyl)-4-amidinophenylalanine piperidide; D005341:Fibrinolysin