Discovery of AZD6642, an inhibitor of 5-lipoxygenase activating protein (FLAP) for the treatment of inflammatory diseases

  • J Med Chem. 2015 Jan 22;58(2):897-911. doi: 10.1021/jm501531v.
Malin Lemurell  1 ,  Johan Ulander ,  Susanne Winiwarter ,  Anders Dahlén ,  Öjvind Davidsson ,  Hans Emtenäs ,  Johan Broddefalk ,  Marianne Swanson ,  Daniel Hovdal ,  Alleyn T Plowright ,  Anna Pettersen ,  Marie Rydén-Landergren ,  Jonas Barlind ,  Antonio Llinas ,  Margareta Herslöf ,  Tomas Drmota ,  Kalle Sigfridsson ,  Sara Moses ,  Carl Whatling
Affiliations
  • 1. Cardiovascular & Metabolic Diseases iMed, ‡Respiratory, Inflammation & Autoimmune Diseases iMed, §Drug Safety & Metabolism, and ∥Pharmaceutical Development, AstraZeneca , Pepparedsleden 1, Mölndal, 43183, Sweden.
PMID: 25478788 DOI: 10.1021/jm501531v
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.

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