Discovery of AZD2716: A Novel Secreted Phospholipase A2 (sPLA2) Inhibitor for the Treatment of Coronary Artery Disease

  • ACS Med Chem Lett. 2016 Aug 9;7(10):884-889. doi: 10.1021/acsmedchemlett.6b00188.
Fabrizio Giordanetto  1 ,  Daniel Pettersen  1 ,  Ingemar Starke  1 ,  Peter Nordberg  1 ,  Mikael Dahlström  1 ,  Laurent Knerr  1 ,  Nidhal Selmi  1 ,  Birgitta Rosengren  1 ,  Lars-Olof Larsson  1 ,  Jenny Sandmark  1 ,  Marie Castaldo  1 ,  Niek Dekker  1 ,  Ulla Karlsson  1 ,  Eva Hurt-Camejo  1
Affiliations
  • 1. Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit Departments of Medicinal Chemistry, Bioscience, DMPK, Discovery Sciences Departments of Structure & Biophysics, Reagents and Assay Development, and Screening Sciences and Sample Management, Astrazeneca, Mölndal , Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
PMID: 27774123 DOI: 10.1021/acsmedchemlett.6b00188
Abstract

Expedited structure-based optimization of the initial fragment hit 1 led to the design of (R)-7 (AZD2716) a novel, potent secreted Phospholipase A2 (sPLA2) inhibitor with excellent preclinical pharmacokinetic properties across species, clear in vivo efficacy, and minimized safety risk. Based on accumulated profiling data, (R)-7 was selected as a clinical candidate for the treatment of coronary artery disease.

Keywords
Secreted phospholipase A2; atherosclerosis; coronary artery disease; fragment screening; fragment-based drug discovery; inhibitor; sPLA2.
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