title: Structure-based design of potent, amidine-derived inhibitors of factor Xa: evaluation of selectivity, anticoagulant activity, and antithrombotic activity.
abstract: To enhance the potency of 1,2-dibenzamidobenzene-derived inhibitors of factor Xa (fXa), an amidine substituent was incorporated on one of the benzoyl side chains to interact with Asp189 in the S1 specificity pocket. Lead molecule 1 was docked into the active site of fXa to facilitate inhibitor design. Subsequently, iterative SAR studies and molecular modeling led to a 1000-fold increase in fXa affinity and a refined model of the new inhibitors in the fXa active site. Strong support for the computational model was achieved through the acquisition of an X-ray crystal structure using thrombin as a surrogate protein. The amidines in this series show high levels of selectivity for the inhibition of fXa relative to other trypsin-like serine proteases. Furthermore, the fXa affinity of compounds in this series (K(ass) = 50-500 x 10(6) L/mol) translates effectively into both anticoagulant activity in vitro and antithrombotic activity in vivo.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA. wileymr@lilly.com
authors.forename: M R
authors.initials: MR
authors.lastname: Wiley
authors.forename: L C
authors.initials: LC
authors.lastname: Weir
authors.forename: S
authors.initials: S
authors.lastname: Briggs
authors.forename: N A
authors.initials: NA
authors.lastname: Bryan
authors.forename: J
authors.initials: J
authors.lastname: Buben
authors.forename: C
authors.initials: C
authors.lastname: Campbell
authors.forename: N Y
authors.initials: NY
authors.lastname: Chirgadze
authors.forename: R C
authors.initials: RC
authors.lastname: Conrad
authors.forename: T J
authors.initials: TJ
authors.lastname: Craft
authors.forename: J V
authors.initials: JV
authors.lastname: Ficorilli
authors.forename: J B
authors.initials: JB
authors.lastname: Franciskovich
authors.forename: L L
authors.initials: LL
authors.lastname: Froelich
authors.forename: D S
authors.initials: DS
authors.lastname: Gifford-Moore
authors.forename: T
authors.initials: T
authors.lastname: Goodson
authors.forename: D K
authors.initials: DK
authors.lastname: Herron
authors.forename: V J
authors.initials: VJ
authors.lastname: Klimkowski
authors.forename: K D
authors.initials: KD
authors.lastname: Kurz
authors.forename: J A
authors.initials: JA
authors.lastname: Kyle
authors.forename: J J
authors.initials: JJ
authors.lastname: Masters
authors.forename: A M
authors.initials: AM
authors.lastname: Ratz
authors.forename: G
authors.initials: G
authors.lastname: Milot
authors.forename: R T
authors.initials: RT
authors.lastname: Shuman
authors.forename: T
authors.initials: T
authors.lastname: Smith
authors.forename: G F
authors.initials: GF
authors.lastname: Smith
authors.forename: A L
authors.initials: AL
authors.lastname: Tebbe
authors.forename: J M
authors.initials: JM
authors.lastname: Tinsley
mesh_terms: D000578:Amidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004285:Dogs; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015951:Factor Xa / Q000737:chemistry / Q000378:metabolism; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008958:Models, Molecular; D011517:Prothrombin Time; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000737:chemistry / Q000378:metabolism; D013927:Thrombosis / Q000188:drug therapy
chemical_list: D000578:Amidines; D000925:Anticoagulants; D004791:Enzyme Inhibitors; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D013917:Thrombin; D015951:Factor Xa