title: Structure-Based Design of Macrocyclic Factor XIa Inhibitors: Discovery of the Macrocyclic Amide Linker.
abstract: A novel series of macrocyclic FXIa inhibitors was designed based on our lead acyclic phenyl imidazole chemotype. Our initial macrocycles, which were double-digit nanomolar FXIa inhibitors, were further optimized with assistance from utilization of structure-based drug design and ligand bound X-ray crystal structures. This effort resulted in the discovery of a macrocyclic amide linker which was found to form a key hydrogen bond with the carbonyl of Leu41 in the FXIa active site, resulting in potent FXIa inhibitors. The macrocyclic FXIa series, exemplified by compound 16, had a FXIa Ki= 0.16 nM with potent anticoagulant activity in an in vitro clotting assay (aPTT EC1.5x= 0.27 μM) and excellent selectivity against the relevant blood coagulation enzymes.
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , P.O. Box 5400, Princeton, New Jersey 08543, United States.
authors.forename: James R
authors.identifier: 0000-0002-4790-597X
authors.initials: JR
authors.lastname: Corte
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , P.O. Box 5400, Princeton, New Jersey 08543, United States.
authors.forename: Tianan
authors.initials: T
authors.lastname: Fang
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , P.O. Box 5400, Princeton, New Jersey 08543, United States.
authors.forename: Honey
authors.initials: H
authors.lastname: Osuna
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , P.O. Box 5400, Princeton, New Jersey 08543, United States.
authors.forename: Donald J P
authors.initials: DJ
authors.lastname: Pinto
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , P.O. Box 5400, Princeton, New Jersey 08543, United States.
authors.forename: Karen A
authors.initials: KA
authors.lastname: Rossi
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , P.O. Box 5400, Princeton, New Jersey 08543, United States.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Myers
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , P.O. Box 5400, Princeton, New Jersey 08543, United States.
authors.forename: Steven
authors.initials: S
authors.lastname: Sheriff
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , P.O. Box 5400, Princeton, New Jersey 08543, United States.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Lou
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , P.O. Box 5400, Princeton, New Jersey 08543, United States.
authors.forename: Joanna J
authors.initials: JJ
authors.lastname: Zheng
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , P.O. Box 5400, Princeton, New Jersey 08543, United States.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Harper
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , P.O. Box 5400, Princeton, New Jersey 08543, United States.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Bozarth
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , P.O. Box 5400, Princeton, New Jersey 08543, United States.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , P.O. Box 5400, Princeton, New Jersey 08543, United States.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Luettgen
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , P.O. Box 5400, Princeton, New Jersey 08543, United States.
authors.forename: Dietmar A
authors.initials: DA
authors.lastname: Seiffert
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , P.O. Box 5400, Princeton, New Jersey 08543, United States.
authors.forename: Carl P
authors.initials: CP
authors.lastname: Decicco
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , P.O. Box 5400, Princeton, New Jersey 08543, United States.
authors.forename: Ruth R
authors.initials: RR
authors.lastname: Wexler
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , P.O. Box 5400, Princeton, New Jersey 08543, United States.
authors.forename: Mimi L
authors.initials: ML
authors.lastname: Quan
mesh_terms: D000577:Amides / Q000737:chemistry*; D055808:Drug Discovery; D015945:Factor XIa / Q000037:antagonists & inhibitors*; D006860:Hydrogen Bonding; D008024:Ligands; D047028:Macrocyclic Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D015394:Molecular Structure; D015842:Serine Proteinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000577:Amides; D008024:Ligands; D047028:Macrocyclic Compounds; D015842:Serine Proteinase Inhibitors; D015945:Factor XIa