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, Philosophenweg 12, D-07743 Jena, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Steinmetzer
authors.forename: A
authors.initials: A
authors.lastname: Schweinitz
authors.forename: S
authors.initials: S
authors.lastname: Künzel
authors.forename: P
authors.initials: P
authors.lastname: Wikström
authors.forename: J
authors.initials: J
authors.lastname: Hauptmann
authors.forename: J
authors.initials: J
authors.lastname: Stürzebecher
mesh_terms: D000818:Animals; D000991:Antithrombins / Q000138:chemical synthesis* / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism* / Q000493:pharmacokinetics; D001646:Bile / Q000737:chemistry; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism* / Q000493:pharmacokinetics; D005260:Female; D005998:Glycine / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism* / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000378:metabolism; D013997:Time Factors
chemical_list: D000991:Antithrombins; D004151:Dipeptides; D010880:Piperidines; C038708:N(alpha)-(2-naphthylsulfonylglycyl)-4-amidinophenylalanine piperidide; D013917:Thrombin; D005998:Glycine