2-(2-Chloro-6-fluorophenyl)acetamides as potent thrombin inhibitors.

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Lee L, Kreutter KD, Pan W, Crysler C, Spurlino J, Player MR, Tomczuk B, Lu T

2-(2-Chloro-6-fluorophenyl)acetamides as potent thrombin inhibitors.

Bioorg Med Chem Lett. 2007 Nov 15;17(22):6266-9. Epub 2007 Sep 8.

PubMed ID

17889527 [ View in PubMed

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Abstract

2-(2-Chloro-6-fluorophenyl)acetamides having 2,2-difluoro-2-aryl/heteroaryl-ethylamine P3 and oxyguanidine P1 substituents are potent thrombin inhibitors (K(i)=0.9-33.9 nM). 2-(5-Chloro-pyridin-2-yl)-2,2-difluoroethylamine was the best P3 substituent, yielding the most potent inhibitor (K(i)=0.7 nM). Replacing the P3 heteroaryl group with a phenyl ring or replacing the difluoro substitution with dimethyl or cyclopropyl groups in the linker reduced the affinity for thrombin significantly. The aminopyridine P1s also provided an increase in potency.

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)	47.1	N/A	N/A	Details