Highly efficacious factor Xa inhibitors containing alpha-substituted phenylcycloalkyl P4 moieties.

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Qiao JX, King SR, He K, Wong PC, Rendina AR, Luettgen JM, Xin B, Knabb RM, Wexler RR, Lam PY

Highly efficacious factor Xa inhibitors containing alpha-substituted phenylcycloalkyl P4 moieties.

Bioorg Med Chem Lett. 2009 Jan 15;19(2):462-8. doi: 10.1016/j.bmcl.2008.11.049. Epub 2008 Nov 18.

PubMed ID

19046881 [ View in PubMed

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Abstract

We previously disclosed a series of highly potent FXa inhibitors bearing alpha-substituted (CH(2)NR(1)R(2)) 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 alpha-substitution (R group) of the cyclopropyl ring on FXa binding affinity (FXa K(i)), human plasma anticoagulant activity (PT EC(2x)) 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 (EC(50)s=29-81nM).

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Apixaban	Coagulation factor X	Ki (nM)	0.08	N/A	N/A	Details