Structure-activity relationships of substituted benzothiophene-anthranilamide factor Xa inhibitors.
Compound 1 was identified by high throughput screening as a novel, potent, non-amidine factor Xa inhibitor with good selectivity against thrombin and trypsin. A series of modifications of the three aromatic groups of 1 was investigated. Substitution of chlorine or bromine for fluorine on the aniline ring led to the discovery of subnanomolar factor Xa inhibitors. Positions on the anthranilic acid ring that can accommodate further substitution were also identified.
Chou
Yuo-Ling
YL
Department of Medicinal Chemistry, Berlex Biosciences, PO Box 4099, Richmond, CA 94804-0099, USA. you-ling_chou@berlex.com
Davey
David D
DD
Eagen
Keith A
KA
Griedel
Brian D
BD
Karanjawala
Rushad
R
Phillips
Gary B
GB
Sacchi
Karna L
KL
Shaw
Kenneth J
KJ
Wu
Shung C
SC
Lentz
Dao
D
Liang
Amy M
AM
Trinh
Lan
L
Morrissey
Michael M
MM
Kochanny
Monica J
MJ
D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis / Q000494:pharmacology; D002417:Cattle; D065427:Factor Xa Inhibitors; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D007202:Indicators and Reagents; D007700:Kinetics; D011517:Prothrombin Time; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*; D013917:Thrombin / Q000037:antagonists & inhibitors; D014361:Trypsin Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D062367:ortho-Aminobenzoates / Q000737:chemistry / Q000494:pharmacology*
D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D006571:Heterocyclic Compounds; D007202:Indicators and Reagents; D015842:Serine Proteinase Inhibitors; D013876:Thiophenes; D014361:Trypsin Inhibitors; D062367:ortho-Aminobenzoates; D013917:Thrombin