کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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1375876 | 981946 | 2009 | 7 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Highly efficacious factor Xa inhibitors containing α-substituted phenylcycloalkyl P4 moieties Highly efficacious factor Xa inhibitors containing α-substituted phenylcycloalkyl P4 moieties](/preview/png/1375876.png)
We previously disclosed a series of highly potent FXa inhibitors bearing α-substituted (CH2NR1R2) phenylcyclopropyl P4 moieties in the pyrazolodihydropyridone core system. Herein, we describe our continuous SAR efforts in this series. Effects of the C-3 substitution of the pyrazolodihydropyridone core and the α-substitution (R group) of the cyclopropyl ring on FXa binding affinity (FXa Ki), human plasma anticoagulant activity (PT EC2×) and permeability are discussed. A set of compounds obtained from optimization of the R group and the C-3 substituent were orally bioavailable in dogs. Furthermore, representative compounds were highly efficacious in the rabbit arterio-venous shunt thrombosis model (EC50s = 29–81 nM).
We previously disclosed a series of highly potent FXa inhibitors bearing α-substituted (CH2NR1R2) phenylcyclopropyl P4 moieties in the pyrazolodihydropyridone core system. Herein, we describe our continuous SAR efforts in this series. Effects of the C-3 substitution of the pyrazolodihydropyridone core and the α-substitution (R group) of the cyclopropyl ring on FXa binding affinity (FXa Ki), human plasma anticoagulant activity (PT EC2×) and permeability are discussed. A set of compounds obtained from optimization of the R group and the C-3 substituent were orally bioavailable in dogs. Furthermore, representative compounds were highly efficacious in the rabbit arterio-venous shunt thrombosis model (EC50s = 29–81 nM).Figure optionsDownload as PowerPoint slide
Journal: Bioorganic & Medicinal Chemistry Letters - Volume 19, Issue 2, 15 January 2009, Pages 462–468