title: 2-(2-Chloro-6-fluorophenyl)acetamides as potent thrombin inhibitors.
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.
authors: Drug Discovery, Johnson & Johnson, Pharmaceutical Research and Development, Spring House, PA, USA.
authors: Lily
authors: L
authors: Lee
authors: Kevin D
authors: KD
authors: Kreutter
authors: Wenxi
authors: W
authors: Pan
authors: Carl
authors: C
authors: Crysler
authors: John
authors: J
authors: Spurlino
authors: Mark R
authors: MR
authors: Player
authors: Bruce
authors: B
authors: Tomczuk
authors: Tianbao
authors: T
authors: Lu
mesh_terms: 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
chemical_list: D000081:Acetamides; D000925:Anticoagulants; D006846:Hydrocarbons, Halogenated; D013917:Thrombin