Design, synthesis and testing of amino-bicycloaryl based orally bioavailable thrombin inhibitors.
Replacement of the highly basic benzamidine moiety with moderate basic amino-bicycloaryl moieties in a series of thrombin inhibitors related to NAPAMP provided potent enzyme inhibition and significant improvements in membrane transport and oral bioavailability.
Rewinkel
J B
JB
NV Organon, Research and Development, Oss, The Netherlands.
Lucas
H
H
Smit
M J
MJ
Noach
A B
AB
van Dinther
T G
TG
Rood
A M
AM
Jenneboer
A J
AJ
van Boeckel
C A
CA
D000284:Administration, Oral; D000925:Anticoagulants / Q000138:chemical synthesis / Q000494:pharmacology; D000991:Antithrombins / Q000138:chemical synthesis* / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000494:pharmacology; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D015195:Drug Design; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis / Q000494:pharmacology; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D013917:Thrombin / Q000037:antagonists & inhibitors*
D000925:Anticoagulants; D000991:Antithrombins; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007546:Isoquinolines; D010880:Piperidines; D015842:Serine Proteinase Inhibitors; D013917:Thrombin