2. Academic Validation
  3. Lead optimization of a pyrazolo[1,5-a]pyrimidin-7(4H)-one scaffold to identify potent, selective and orally bioavailable KDM5 inhibitors suitable for in vivo biological studies

Lead optimization of a pyrazolo[1,5-a]pyrimidin-7(4H)-one scaffold to identify potent, selective and orally bioavailable KDM5 inhibitors suitable for in vivo biological studies

  • Bioorg Med Chem Lett. 2016 Aug 15;26(16):4036-41. doi: 10.1016/j.bmcl.2016.06.078.
Jun Liang 1,  Birong Zhang 2,  Sharada Labadie 2,  Daniel F Ortwine 2,  Maia Vinogradova 2,  James R Kiefer 2,  Victor S Gehling 3,  Jean-Christophe Harmange 3,  Richard Cummings 3,  Tommy Lai 4,  Jiangpeng Liao 4,  Xiaoping Zheng 4,  Yichin Liu 2,  Amy Gustafson 2,  Erica Van der Porten 2,  Weifeng Mao 4,  Bianca M Liederer 2,  Gauri Deshmukh 2,  Marie Classon 2,  Patrick Trojer 3,  Peter S Dragovich 2,  Lesley Murray 2
Affiliations

Affiliations

  • 1 Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: liang.jun@gene.com.
  • 2 Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
  • 3 Constellation Pharmaceuticals Inc., 215 First Street, Suite 200, Cambridge, MA 02142, USA.
  • 4 WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
PMID: 27406798 DOI: 10.1016/j.bmcl.2016.06.078
Abstract

Starting with a lead [1,5-a]pyrimidin-7(4H)-one-containing molecule (1), we generated potent, selective and orally bioavailable KDM5 inhibitors. Using structure- and property-based approaches, we designed 48 with improved cell potency (PC9 H3K4Me3 EC50=0.34μM). Furthermore, 48 maintained suitable physiochemical properties and displayed an excellent pharmacokinetic (PK) profile in mice. When dosed orally in mice at 50mg/kg twice a day (BID), 48 showed an unbound maximal plasma concentration (Cmax) >15-fold over its cell EC50, thereby providing a robust chemical probe for studying KDM5 biological functions in vivo.

Keywords

Drug resistance; Epigenetics; Histone demethylase; KDM5; Lead optimization; Selective KDM5 inhibitors.

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