title: Design, synthesis and biological evaluation of selective boron-containing thrombin inhibitors.
abstract: Based on the structural comparison of the S-1 pocket in different trypsin-like serine proteases, a series of Boc-D-trimethylsilylalanine-proline-boro-X pinanediol derivatives, with boro-X being different amino boronic acids, have been synthesised as inhibitors of thrombin. The influence of hydrogen donor/acceptor properties of different residues in the P-1 side chain of these inhibitors on the selectivity profile has been investigated. This study confirmed the structure-based working hypothesis: The hydrophobic/hydrophilic character of amino acid residues 190 and 213 in the neighbourhood of Asp 189 in the S-1 pocket of thrombin (Ala/Val), trypsin (Ser/Val) and plasmin (Ser/Thr) define the specificity for the interaction with different P-1 residues of the inhibitors. Many of the synthesised compounds demonstrate potent antithrombin activity with Boc-D-trimethylsilylalanine-proline-boro-methoxypropylglycine++ + pinanediol (9) being the most selective thrombin inhibitor of this series.
authors.affiliation: Novartis Pharma AG, Research, Basel, Switzerland. anette.wienand@pharma.novartis.com
authors.forename: A
authors.initials: A
authors.lastname: Wienand
authors.forename: C
authors.initials: C
authors.lastname: Ehrhardt
authors.forename: R
authors.initials: R
authors.lastname: Metternich
authors.forename: C
authors.initials: C
authors.lastname: Tapparelli
mesh_terms: D001665:Binding Sites; D001896:Boron Compounds / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology*; D004151:Dipeptides / Q000737:chemistry; D015195:Drug Design; D005341:Fibrinolysin / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D014361:Trypsin Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D001896:Boron Compounds; D004151:Dipeptides; D009842:Oligopeptides; D015842:Serine Proteinase Inhibitors; D014361:Trypsin Inhibitors; C121615:tert-butoxycarbonyl-trimethylsilylalanyl-prolyl-boro-methoxypropylglycine-pinanediol; D013917:Thrombin; D005341:Fibrinolysin