title: Creating novel activated factor XI inhibitors through fragment based lead generation and structure aided drug design.
abstract: Activated factor XI (FXIa) inhibitors are anticipated to combine anticoagulant and profibrinolytic effects with a low bleeding risk. This motivated a structure aided fragment based lead generation campaign to create novel FXIa inhibitor leads. A virtual screen, based on docking experiments, was performed to generate a FXIa targeted fragment library for an NMR screen that resulted in the identification of fragments binding in the FXIa S1 binding pocket. The neutral 6-chloro-3,4-dihydro-1H-quinolin-2-one and the weakly basic quinolin-2-amine structures are novel FXIa P1 fragments. The expansion of these fragments towards the FXIa prime side binding sites was aided by solving the X-ray structures of reported FXIa inhibitors that we found to bind in the S1-S1'-S2' FXIa binding pockets. Combining the X-ray structure information from the identified S1 binding 6-chloro-3,4-dihydro-1H-quinolin-2-one fragment and the S1-S1'-S2' binding reference compounds enabled structure guided linking and expansion work to achieve one of the most potent and selective FXIa inhibitors reported to date, compound 13, with a FXIa IC50 of 1.0 nM. The hydrophilicity and large polar surface area of the potent S1-S1'-S2' binding FXIa inhibitors compromised permeability. Initial work to expand the 6-chloro-3,4-dihydro-1H-quinolin-2-one fragment towards the prime side to yield molecules with less hydrophilicity shows promise to afford potent, selective and orally bioavailable compounds.
authors: Medicinal Chemistry, Cardiovascular & Metabolic Diseases Innovative Medicines, AstraZeneca R&D, Mölndal, Sweden.
authors: Ola
authors: O
authors: Fjellström
authors: Medicinal Chemistry, Cardiovascular & Metabolic Diseases Innovative Medicines, AstraZeneca R&D, Mölndal, Sweden.
authors: Sibel
authors: S
authors: Akkaya
authors: Medicinal Chemistry, Cardiovascular & Metabolic Diseases Innovative Medicines, AstraZeneca R&D, Mölndal, Sweden.
authors: Hans-Georg
authors: HG
authors: Beisel
authors: Discovery Sciences, AstraZeneca R&D, Mölndal, Sweden.
authors: Per-Olof
authors: PO
authors: Eriksson
authors: Medicinal Chemistry, Cardiovascular & Metabolic Diseases Innovative Medicines, AstraZeneca R&D, Mölndal, Sweden.
authors: Karl
authors: K
authors: Erixon
authors: Bioscience, Cardiovascular & Metabolic Diseases Innovative Medicines, AstraZeneca R&D, Mölndal, Sweden.
authors: David
authors: D
authors: Gustafsson
authors: Drug Metabolism and Pharmacokinetics, Cardiovascular & Metabolic Diseases Innovative Medicines, AstraZeneca R&D, Mölndal, Sweden.
authors: Ulrik
authors: U
authors: Jurva
authors: Bioscience, Cardiovascular & Metabolic Diseases Innovative Medicines, AstraZeneca R&D, Mölndal, Sweden.
authors: Daiwu
authors: D
authors: Kang
authors: Medicinal Chemistry, Cardiovascular & Metabolic Diseases Innovative Medicines, AstraZeneca R&D, Mölndal, Sweden.
authors: David
authors: D
authors: Karis
authors: Bioscience, Cardiovascular & Metabolic Diseases Innovative Medicines, AstraZeneca R&D, Mölndal, Sweden.
authors: Wolfgang
authors: W
authors: Knecht
authors: Bioscience, Cardiovascular & Metabolic Diseases Innovative Medicines, AstraZeneca R&D, Mölndal, Sweden.
authors: Viveca
authors: V
authors: Nerme
authors: Medicinal Chemistry, Cardiovascular & Metabolic Diseases Innovative Medicines, AstraZeneca R&D, Mölndal, Sweden.
authors: Ingemar
authors: I
authors: Nilsson
authors: Medicinal Chemistry, Cardiovascular & Metabolic Diseases Innovative Medicines, AstraZeneca R&D, Mölndal, Sweden.
authors: Thomas
authors: T
authors: Olsson
authors: Medicinal Chemistry, Cardiovascular & Metabolic Diseases Innovative Medicines, AstraZeneca R&D, Mölndal, Sweden.
authors: Alma
authors: A
authors: Redzic
authors: Discovery Sciences, AstraZeneca R&D, Mölndal, Sweden.
authors: Robert
authors: R
authors: Roth
authors: Discovery Sciences, AstraZeneca R&D, Mölndal, Sweden.
authors: Jenny
authors: J
authors: Sandmark
authors: Discovery Sciences, AstraZeneca R&D, Mölndal, Sweden.
authors: Anna
authors: A
authors: Tigerström
authors: Discovery Sciences, AstraZeneca R&D, Mölndal, Sweden.
authors: Linda
authors: L
authors: Öster
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D015945:Factor XIa / Q000037:antagonists & inhibitors / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D019151:Peptide Library; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D015842:Serine Proteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D008024:Ligands; D019151:Peptide Library; D015842:Serine Proteinase Inhibitors; D015945:Factor XIa
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