title: Tetrahydro-isoquinoline-based factor Xa inhibitors.
abstract: Derivatives of (2-amidino-1,2,3, 4-tetrahydro-isoquinolin-7-yloxy)phenylacetic acid (TIPAC) were developed as inhibitors of factor Xa (fXa). The compounds are prepared using 15 synthetic steps on average. The most potent compounds (14, 17, 22-26) display inhibition constants of Ki = 21-55 nM but do not inhibit thrombin (Ki = 5->100 microM) and only weakly inhibit trypsin (Ki = 0.08-5 microM). They bear a second basic moiety, e.g., substituted 1-(iminomethyl)piperidines, which is linked to C-4 of the phenyl group of TIPAC via an oxygen atom. The inhibition constants of these compounds are almost independent of the size of the (iminomethyl)piperidine substituent. Due to the fact that fXa displays two cation binding sites, namely, the S1 and S4 sites, in principle two binding modes are conceivable for the novel dibasic fXa inhibitors. Molecular modeling experiments based on the X-ray structures of uninhibited fXa and the DX-9065a/fXa complex were carried out. The results taken together with the inhibition constants clearly favor one binding mode: the tetrahydro-isoquinoline fills the S1 pocket even better than the naphthalene moiety of DX-9065a, and the (iminomethyl)piperidine residues occupy the S4 site.
authors.affiliation: Chemical Research Department, Boehringer Mannheim GmbH, D-68298 Mannheim, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Kucznierz
authors.forename: F
authors.initials: F
authors.lastname: Grams
authors.forename: H
authors.initials: H
authors.lastname: Leinert
authors.forename: K
authors.initials: K
authors.lastname: Marzenell
authors.forename: R A
authors.initials: RA
authors.lastname: Engh
authors.forename: W
authors.initials: W
authors.lastname: von der Saal
mesh_terms: D000925:Anticoagulants / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015951:Factor Xa / Q000378:metabolism; D065427:Factor Xa Inhibitors; D005341:Fibrinolysin / Q000037:antagonists & inhibitors; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D007700:Kinetics; D008958:Models, Molecular; D008970:Molecular Weight; D010314:Partial Thromboplastin Time; D011485:Protein Binding; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013917:Thrombin / Q000037:antagonists & inhibitors; D013918:Thrombin Time; D014361:Trypsin Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D007546:Isoquinolines; D015842:Serine Proteinase Inhibitors; D014361:Trypsin Inhibitors; D013917:Thrombin; D015951:Factor Xa; D005341:Fibrinolysin