title: Discovery of AZD6642, an inhibitor of 5-lipoxygenase activating protein (FLAP) for the treatment of inflammatory diseases.
abstract: A drug discovery program in search of novel 5-lipoxygenase activating protein (FLAP) inhibitors focused on driving a reduction in lipophilicity with maintained or increased ligand lipophilic efficiency (LLE) compared to previously reported compounds led to the discovery of AZD6642 (15b). Introduction of a hydrophilic tetrahydrofuran (THF) ring at the stereogenic central carbon atom led to a significant shift in physicochemical property space. The structure-activity relationship exploration and optimization of DMPK properties leading to this compound are described in addition to pharmacokinetic analysis and an investigation of the pharmacokinetic (PK)-pharmacodynamic (PD) relationship based on ex vivo leukotriene B4 (LTB4) levels in dog. AZD6642 shows high specific potency and low lipophilicity, resulting in a selective and metabolically stable profile. On the basis of initial PK/PD relation measured, a low dose to human was predicted.
authors.affiliation: Cardiovascular & Metabolic Diseases iMed, ‡Respiratory, Inflammation & Autoimmune Diseases iMed, §Drug Safety & Metabolism, and ∥Pharmaceutical Development, AstraZeneca , Pepparedsleden 1, Mölndal, 43183, Sweden.
authors.forename: Malin
authors.initials: M
authors.lastname: Lemurell
authors.forename: Johan
authors.initials: J
authors.lastname: Ulander
authors.forename: Susanne
authors.initials: S
authors.lastname: Winiwarter
authors.forename: Anders
authors.initials: A
authors.lastname: Dahlén
authors.forename: Öjvind
authors.initials: Ö
authors.lastname: Davidsson
authors.forename: Hans
authors.initials: H
authors.lastname: Emtenäs
authors.forename: Johan
authors.initials: J
authors.lastname: Broddefalk
authors.forename: Marianne
authors.initials: M
authors.lastname: Swanson
authors.forename: Daniel
authors.initials: D
authors.lastname: Hovdal
authors.forename: Alleyn T
authors.initials: AT
authors.lastname: Plowright
authors.forename: Anna
authors.initials: A
authors.lastname: Pettersen
authors.forename: Marie
authors.initials: M
authors.lastname: Rydén-Landergren
authors.forename: Jonas
authors.initials: J
authors.lastname: Barlind
authors.forename: Antonio
authors.initials: A
authors.lastname: Llinas
authors.forename: Margareta
authors.initials: M
authors.lastname: Herslöf
authors.forename: Tomas
authors.initials: T
authors.lastname: Drmota
authors.forename: Kalle
authors.initials: K
authors.lastname: Sigfridsson
authors.forename: Sara
authors.initials: S
authors.lastname: Moses
authors.forename: Carl
authors.initials: C
authors.lastname: Whatling
mesh_terms: D058946:5-Lipoxygenase-Activating Protein Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D004285:Dogs; D055808:Drug Discovery; D006801:Humans; D010848:Picolinic Acids / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D011719:Pyrazines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D051381:Rats; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
chemical_list: C000596370:5-(2-(4-(5-aminopyrazin-2-yl)phenyl)tetrahydrofuran-2-yl)-N-(2-hydroxy-2-methylpropyl)pyridine-2-carboxamide; D058946:5-Lipoxygenase-Activating Protein Inhibitors; D000893:Anti-Inflammatory Agents; D010848:Picolinic Acids; D011719:Pyrazines