title: A Bisbenzamidine Phosphonate as a Janus-faced Inhibitor for Trypsin-like Serine Proteases.
abstract: A hybrid approach was applied for the design of an inhibitor of trypsin-like serine proteases. Compound 16 [(R,R)- and (R,S)-diphenyl (4-(1-(4-amidinobenzylamino)-1-oxo-3-phenylpropan-2-ylcarbamoyl)phenylamino)(4-amidinophenyl)methylphosphonate hydrochloride], prepared in a convergent synthetic procedure, possesses a phosphonate warhead prone to react with the active site serine residue in a covalent, irreversible manner. Each of the two benzamidine moieties of 16 can potentially be accommodated in the S1 pocket of the target enzyme, but only the benzamidine close to the phosphonate group would then promote an irreversible interaction. The Janus-faced inhibitor 16 was evaluated against several serine proteases and caused a pronounced inactivation of human thrombin with a second-order rate constant (kinac /Ki) of 59 500 M(-1)  s(-1). With human matriptase, 16 showed preference for a reversible mode of inhibition (IC50 =2.6 μM) as indicated by linear progress curves and enzyme reactivation.
authors: Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn (Germany).
authors: Daniela
authors: D
authors: Häußler
authors: Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn (Germany).
authors: Tamara
authors: T
authors: Scheidt
authors: Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn (Germany).
authors: Marit
authors: M
authors: Stirnberg
authors: Institute of Pharmaceutical Chemistry, Philipps University Marburg, Marbacher Weg 6, 35032 Marburg (Germany).
authors: Torsten
authors: T
authors: Steinmetzer
authors: Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn (Germany). guetschow@uni-bonn.de.
authors: Michael
authors: M
authors: Gütschow
mesh_terms: D001550:Benzamidines / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D015394:Molecular Structure; D063065:Organophosphonates / Q000737:chemistry / Q000494:pharmacology*; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D001550:Benzamidines; D063065:Organophosphonates; D015842:Serine Proteinase Inhibitors; C114880:trypsin-like serine protease; D012697:Serine Endopeptidases; C485596:ST14 protein, human; D013917:Thrombin; C032157:benzamidine
keywords: benzamidines; enzyme inhibition; hybrid compounds; phosphonates; serine proteases