Orally efficacious thrombin inhibitors with cyanofluorophenylacetamide as the P2 motif.

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Kreutter KD, Lu T, Lee L, Giardino EC, Patel S, Huang H, Xu G, Fitzgerald M, Haertlein BJ, Mohan V, Crysler C, Eisennagel S, Dasgupta M, McMillan M, Spurlino JC, Huebert ND, Maryanoff BE, Tomczuk BE, Damiano BP, Player MR

Orally efficacious thrombin inhibitors with cyanofluorophenylacetamide as the P2 motif.

Bioorg Med Chem Lett. 2008 May 1;18(9):2865-70. doi: 10.1016/j.bmcl.2008.03.087. Epub 2008 Apr 8.

PubMed ID

18420408 [ View in PubMed

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Abstract

2-Cyano-6-fluorophenylacetamide was explored as a novel P2 scaffold in the design of thrombin inhibitors. Optimization around this structural motif culminated in 14, which is a potent thrombin inhibitor (K(i)=1.2nM) that exhibits robust efficacy in canine anticoagulation and thrombosis models upon oral administration.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
N-[2-({[amino(imino)methyl]amino}oxy)ethyl]-2-{6-chloro-3-[(2,2-difluoro-2-phenylethyl)amino]-2-fluorophenyl}acetamide	Prothrombin	Ki (nM)	47	N/A	N/A	Details
N-[2-(carbamimidamidooxy)ethyl]-2-{6-cyano-3-[(2,2-difluoro-2-pyridin-2-ylethyl)amino]-2-fluorophenyl}acetamide	Prothrombin	Ki (nM)	1.2	N/A	N/A	Details