2-(2-Chloro-6-fluorophenyl)acetamides as potent thrombin inhibitors.
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.
Lee
Lily
L
Drug Discovery, Johnson & Johnson, Pharmaceutical Research and Development, Spring House, PA, USA.
Kreutter
Kevin D
KD
Pan
Wenxi
W
Crysler
Carl
C
Spurlino
John
J
Player
Mark R
MR
Tomczuk
Bruce
B
Lu
Tianbao
T
D000081:Acetamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000925:Anticoagulants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D006801:Humans; D006846:Hydrocarbons, Halogenated / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000737:chemistry
D000081:Acetamides; D000925:Anticoagulants; D006846:Hydrocarbons, Halogenated; D013917:Thrombin