title: Discovery of Phenylglycine Lactams as Potent Neutral Factor VIIa Inhibitors.
abstract: Inhibitors of Factor VIIa (FVIIa), a serine protease in the clotting cascade, have shown strong antithrombotic efficacy in preclinical thrombosis models with minimal bleeding liabilities. Discovery of potent, orally active FVIIa inhibitors has been largely unsuccessful because known chemotypes have required a highly basic group in the S1 binding pocket for high affinity. A recently reported fragment screening effort resulted in the discovery of a neutral heterocycle, 7-chloro-3,4-dihydroisoquinolin-1(2H)-one, that binds in the S1 pocket of FVIIa and can be incorporated into a phenylglycine FVIIa inhibitor. Optimization of this P1 binding group led to the first series of neutral, permeable FVIIa inhibitors with low nanomolar potency.
authors.affiliation: Bristol-Myers Squibb R&D , 350 Carter Road, Hopewell Township, 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 Township, New Jersey 08540, United States.
authors.forename: Brandon L
authors.initials: BL
authors.lastname: Parkhurst
authors.affiliation: Bristol-Myers Squibb R&D , 350 Carter Road, Hopewell Township, 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 Township, New Jersey 08540, United States.
authors.forename: Indawati
authors.initials: I
authors.lastname: DeLucca
authors.affiliation: Bristol-Myers Squibb R&D , 350 Carter Road, Hopewell Township, 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 Township, 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 Township, 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, United States.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Bozarth
authors.affiliation: Bristol-Myers Squibb R&D , 311 Pennington Rocky Hill Road, Pennington, New Jersey 08534, 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, United States.
authors.forename: Anzhi
authors.initials: A
authors.lastname: Wei
authors.affiliation: Bristol-Myers Squibb R&D , 311 Pennington Rocky Hill Road, Pennington, New Jersey 08534, 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, United States.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Bristol-Myers Squibb R&D , 311 Pennington Rocky Hill Road, Pennington, New Jersey 08534, 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, United States.
authors.forename: Dietmar A
authors.initials: DA
authors.lastname: Seiffert
authors.affiliation: Bristol-Myers Squibb R&D , 350 Carter Road, Hopewell Township, 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 Township, New Jersey 08540, United States.
authors.forename: E Scott
authors.initials: ES
authors.lastname: Priestley
keywords: TF-FVIIa inhibitor; anticoagulant; fragment-based drug design; neutral P1