2. Academic Validation
  3. Optimization of a Series of Bivalent Triazolopyridazine Based Bromodomain and Extraterminal Inhibitors: The Discovery of (3R)-4-[2-[4-[1-(3-Methoxy-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-4-piperidyl]phenoxy]ethyl]-1,3-dimethyl-piperazin-2-one (AZD5153)

Optimization of a Series of Bivalent Triazolopyridazine Based Bromodomain and Extraterminal Inhibitors: The Discovery of (3R)-4-[2-[4-[1-(3-Methoxy-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-4-piperidyl]phenoxy]ethyl]-1,3-dimethyl-piperazin-2-one (AZD5153)

  • J Med Chem. 2016 Sep 8;59(17):7801-17. doi: 10.1021/acs.jmedchem.6b00070.
Robert H Bradbury 1,  Rowena Callis 1,  Gregory R Carr 1,  Huawei Chen 2,  Edwin Clark 2,  Lyman Feron 1,  Steve Glossop 1,  Mark A Graham 1,  Maureen Hattersley 2,  Chris Jones 1,  Scott G Lamont 1,  Gilles Ouvry 3,  Anil Patel 1,  Joe Patel 2,  Alfred A Rabow 1,  Craig A Roberts 1,  Stephen Stokes 1,  Natalie Stratton 1,  Graeme E Walker 1,  Lara Ward 1,  David Whalley 1,  David Whittaker 1,  Gail Wrigley 1,  Michael J Waring 1 4
Affiliations

Affiliations

  • 1 AstraZeneca, Mereside , Alderley Park, Macclesfield, Cheshire SK10 4TG, U.K.
  • 2 AstraZeneca , Gatehouse Park, Waltham, Massachusetts 02451, United States.
  • 3 AstraZeneca , Chemin du Moulin de Vrilly, 51100 Reims, France.
  • 4 Northern Institute for Cancer Research, School of Chemistry, Newcastle University , Bedson Building, Newcastle upon Tyne NE1 7RU, U.K.
PMID: 27528113 DOI: 10.1021/acs.jmedchem.6b00070
Abstract

Here we report the discovery and optimization of a series of bivalent bromodomain and extraterminal inhibitors. Starting with the observation of BRD4 activity of compounds from a previous program, the compounds were optimized for BRD4 potency and physical properties. The optimized compound from this campaign exhibited excellent pharmacokinetic profile and exhibited high potency in vitro and in vivo effecting c-Myc downregulation and tumor growth inhibition in xenograft studies. This compound was selected as the development candidate, AZD5153. The series showed enhanced potency as a result of bivalent binding and a clear correlation between BRD4 activity and cellular potency.

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  • HY-100653
    BET抑制剂
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