title: Discovery of a Highly Potent, Selective, and Orally Bioavailable Macrocyclic Inhibitor of Blood Coagulation Factor VIIa-Tissue Factor Complex.
abstract: Inhibitors of the tissue factor (TF)/factor VIIa complex (TF-FVIIa) are promising novel anticoagulants which show excellent efficacy and minimal bleeding in preclinical models. Starting with an aminoisoquinoline P1-based macrocyclic inhibitor, optimization of the P' groups led to a series of highly potent and selective TF-FVIIa inhibitors which displayed poor permeability. Fluorination of the aminoisoquinoline reduced the basicity of the P1 group and significantly improved permeability. The resulting lead compound was highly potent, selective, and achieved good pharmacokinetics in dogs with oral dosing. Moreover, it demonstrated robust antithrombotic activity in a rabbit model of arterial thrombosis.
authors.affiliation: Bristol-Myers Squibb R&D , 350 Carter Road, Hopewell, New Jersey 08540, United States.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Bristol-Myers Squibb R&D , 350 Carter Road, Hopewell, New Jersey 08540, United States.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Glunz
authors.affiliation: Bristol-Myers Squibb R&D , 350 Carter Road, Hopewell, New Jersey 08540, United States.
authors.forename: James A
authors.initials: JA
authors.lastname: Johnson
authors.affiliation: Bristol-Myers Squibb R&D , 350 Carter Road, Hopewell, New Jersey 08540, United States.
authors.forename: Wen
authors.initials: W
authors.lastname: Jiang
authors.affiliation: Bristol-Myers Squibb R&D , 350 Carter Road, Hopewell, New Jersey 08540, United States.
authors.forename: Swanee
authors.initials: S
authors.lastname: Jacutin-Porte
authors.affiliation: Bristol-Myers Squibb R&D , 350 Carter Road, Hopewell, New Jersey 08540, United States.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Ladziata
authors.affiliation: Bristol-Myers Squibb R&D , 350 Carter Road, Hopewell, New Jersey 08540, United States.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Bristol-Myers Squibb R&D , 350 Carter Road, Hopewell, New Jersey 08540, United States.
authors.forename: Monique S
authors.initials: MS
authors.lastname: Phillips
authors.affiliation: Bristol-Myers Squibb R&D , 350 Carter Road, Hopewell, New Jersey 08540, United States.
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: Wurtz
authors.affiliation: Bristol-Myers Squibb R&D , 350 Carter Road, Hopewell, New Jersey 08540, United States.
authors.forename: Brandon
authors.initials: B
authors.lastname: Parkhurst
authors.affiliation: Bristol-Myers Squibb R&D , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534-2130, United States.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Rendina
authors.affiliation: Bristol-Myers Squibb R&D , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534-2130, United States.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Harper
authors.affiliation: Bristol-Myers Squibb R&D , 350 Carter Road, Hopewell, New Jersey 08540, United States.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Cheney
authors.affiliation: Bristol-Myers Squibb R&D , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534-2130, United States.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Luettgen
authors.affiliation: Bristol-Myers Squibb R&D , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534-2130, United States.
authors.forename: Pancras C
authors.initials: PC
authors.lastname: Wong
authors.affiliation: Bristol-Myers Squibb R&D , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534-2130, United States.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Seiffert
authors.affiliation: Bristol-Myers Squibb R&D , 350 Carter Road, Hopewell, New Jersey 08540, United States.
authors.forename: Ruth R
authors.initials: RR
authors.lastname: Wexler
authors.affiliation: Bristol-Myers Squibb R&D , 350 Carter Road, Hopewell, New Jersey 08540, United States.
authors.forename: E Scott
authors.initials: ES
authors.lastname: Priestley
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001682:Biological Availability; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D015942:Factor VIIa / Q000037:antagonists & inhibitors* / Q000378:metabolism; D064368:Healthy Volunteers; D006801:Humans; D047028:Macrocyclic Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D011817:Rabbits; D013329:Structure-Activity Relationship; D013925:Thromboplastin / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000925:Anticoagulants; D047028:Macrocyclic Compounds; D013925:Thromboplastin; D015942:Factor VIIa