2. Academic Validation
  3. Design and evaluation of novel 8-oxo-pyridopyrimidine Jak1/2 inhibitors

Design and evaluation of novel 8-oxo-pyridopyrimidine Jak1/2 inhibitors

  • Bioorg Med Chem Lett. 2013 Nov 1;23(21):5923-30. doi: 10.1016/j.bmcl.2013.08.082.
Sharada Labadie 1,  Kathy Barrett,  Wade S Blair,  Christine Chang,  Gauri Deshmukh,  Charles Eigenbrot,  Paul Gibbons,  Adam Johnson,  Jane R Kenny,  Pawan Bir Kohli,  Marya Liimatta,  Patrick J Lupardus,  Steven Shia,  Micah Steffek,  Savita Ubhayakar,  Anne van Abbema,  Mark Zak
Affiliations

Affiliation

  • 1 Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: sharadal@gene.com.
PMID: 24042009 DOI: 10.1016/j.bmcl.2013.08.082
Abstract

A highly ligand efficient, novel 8-oxo-pyridopyrimidine containing inhibitor of JAK1 and JAK2 isoforms with a pyridone moiety as the hinge-binding motif was discovered. Structure-based design strategies were applied to significantly improve enzyme potency and the polarity of the molecule was adjusted to gain cellular activity. The crystal structures of two representative inhibitors bound to JAK1 were obtained to enable SAR exploration.

Keywords

8-Oxo-pyridopyrimidines; Hematopoiesis; JAK inhibitors; Rheumatoid arthritis.

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