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
  • 1. Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: [email protected].
  • 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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