Design, synthesis and testing of amino-bicycloaryl based orally bioavailable thrombin inhibitors

J B Rewinkel; H Lucas; M J Smit; A B Noach; T G van Dinther; A M Rood; A J Jenneboer; C A van Boeckel

doi:10.1016/s0960-894x(99)00483-7

Design, synthesis and testing of amino-bicycloaryl based orally bioavailable thrombin inhibitors

Bioorg Med Chem Lett. 1999 Oct 4;9(19):2837-42. doi: 10.1016/s0960-894x(99)00483-7.

Authors

J B Rewinkel¹, H Lucas, M J Smit, A B Noach, T G van Dinther, A M Rood, A J Jenneboer, C A van Boeckel

Affiliation

¹ NV Organon, Research and Development, Oss, The Netherlands.

PMID: 10522702
DOI: 10.1016/s0960-894x(99)00483-7

Abstract

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.

MeSH terms

Administration, Oral
Anticoagulants / chemical synthesis
Anticoagulants / pharmacology
Antithrombins / chemical synthesis*
Antithrombins / pharmacology
Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis*
Bridged Bicyclo Compounds, Heterocyclic / pharmacology
Caco-2 Cells
Cell Membrane Permeability
Drug Design
Humans
Isoquinolines / chemical synthesis
Isoquinolines / pharmacology
Molecular Structure
Piperidines / chemical synthesis
Piperidines / pharmacology
Serine Proteinase Inhibitors / chemical synthesis
Serine Proteinase Inhibitors / pharmacology
Thrombin / antagonists & inhibitors*

Substances

Anticoagulants
Antithrombins
Bridged Bicyclo Compounds, Heterocyclic
Isoquinolines
Piperidines
Serine Proteinase Inhibitors
Thrombin