2. Academic Validation
  3. Discovery of a highly potent orally bioavailable imidazo-[1, 2-a]pyrazine Aurora inhibitor

Discovery of a highly potent orally bioavailable imidazo-[1, 2-a]pyrazine Aurora inhibitor

  • Bioorg Med Chem Lett. 2018 May 1;28(8):1397-1403. doi: 10.1016/j.bmcl.2018.02.037.
Tao Yu 1,  Yonglian Zhang 2,  Angela D Kerekes 2,  Jayaram R Tagat 2,  Ronald J Doll 2,  Yushi Xiao 2,  Sara Esposite 2,  Alan Hruza 3,  David B Belanger 4,  Matthew Voss 5,  Matthew P Rainka 5,  Andrea Basso 6,  Ming Liu 6,  Lianzhu Liang 6,  Ning Sui 6,  Daniel Prelusky 7,  Diane Rindgen 7,  Likang Zhang 2
Affiliations

Affiliations

  • 1 Department of Chemical Research, MRL 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: [email protected].
  • 2 Department of Chemical Research, MRL 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • 3 Department of Structural Chemistry, MRL 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • 4 Department of Chemical Research, MRL 320 Bent Street, Cambridge, MA 02141, USA.
  • 5 AMRI, 26 Corporate Circle, PO Box 15098, Albany, NY 12212, USA.
  • 6 Department of Oncology, MRL 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • 7 Department of DMPK, MRL 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
PMID: 29545102 DOI: 10.1016/j.bmcl.2018.02.037
Abstract

Imidazo-[1, 2-a]pyrazine 1 is a potent inhibitor of Aurora A and B kinase in vitro and is effective in in vivo tumor models, but has poor oral bioavailbility and is unsuitable for oral dosing. We describe herein our effort to improve oral exposure in this class, resulting ultimately in the identification of a potent Aurora inhibitor 16, which exhibited good drug exposure levels across species upon oral dosing, and showed excellent in vivo efficacy in a mouse xenograft tumor model when dosed orally.

Keywords

Aurora inhibitor; Imidazopyrazine; Kinase inhibitor.

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