Aminoisoquinolines: design and synthesis of an orally active benzamidine isostere for the inhibition of factor XA

Y M Choi-Sledeski; M R Becker; D M Green; R Davis; W R Ewing; H J Mason; C Ly; A Spada; G Liang; D Cheney; J Barton; V Chu; K Brown; D Colussi; R Bentley; R Leadley; C Dunwiddie; H W Pauls

doi:10.1016/s0960-894x(99)00421-7

Aminoisoquinolines: design and synthesis of an orally active benzamidine isostere for the inhibition of factor XA

Bioorg Med Chem Lett. 1999 Sep 6;9(17):2539-44. doi: 10.1016/s0960-894x(99)00421-7.

Authors

Y M Choi-Sledeski¹, M R Becker, D M Green, R Davis, W R Ewing, H J Mason, C Ly, A Spada, G Liang, D Cheney, J Barton, V Chu, K Brown, D Colussi, R Bentley, R Leadley, C Dunwiddie, H W Pauls

Affiliation

¹ Department of Medicinal Chemistry, Rhône-Poulenc Rorer, Collegeville, PA 19426, USA.

PMID: 10498204
DOI: 10.1016/s0960-894x(99)00421-7

Abstract

The design, synthesis and SAR of sulfonamidopyrrolidinone fXa inhibitors incorporating a new benzamidine isostere, namely aminoisoquinolines, is described. These inhibitors have higher Caco-2 cell permeability than comparable benzamidines and attain higher levels of exposure upon oral dosing. The most potent member 14b (fXa Ki=6 nM) is selective against other serine proteases of interest (>600 fold).

MeSH terms

Administration, Oral
Animals
Binding Sites
Dogs
Factor Xa Inhibitors*
Isoquinolines / administration & dosage
Isoquinolines / chemical synthesis*
Isoquinolines / pharmacology
Serine Proteinase Inhibitors / administration & dosage
Serine Proteinase Inhibitors / chemical synthesis*
Serine Proteinase Inhibitors / pharmacology
Structure-Activity Relationship

Substances

Factor Xa Inhibitors
Isoquinolines
Serine Proteinase Inhibitors