2. Academic Validation
  3. Discovery of 2-(6-{[(6-fluoroquinolin-2-yl)methyl]amino}bicyclo[3.1.0]hex-3-yl)-N-hydroxypyrimidine-5-carboxamide (CHR-3996), a class I selective orally active histone deacetylase inhibitor

Discovery of 2-(6-{[(6-fluoroquinolin-2-yl)methyl]amino}bicyclo[3.1.0]hex-3-yl)-N-hydroxypyrimidine-5-carboxamide (CHR-3996), a class I selective orally active histone deacetylase inhibitor

  • J Med Chem. 2010 Dec 23;53(24):8663-78. doi: 10.1021/jm101177s.
David Moffat 1,  Sanjay Patel,  Francesca Day,  Andrew Belfield,  Alastair Donald,  Martin Rowlands,  Judata Wibawa,  Deborah Brotherton,  Lindsay Stimson,  Vanessa Clark,  Jo Owen,  Lindsay Bawden,  Gary Box,  Elisabeth Bone,  Paul Mortenson,  Anthea Hardcastle,  Sandra van Meurs,  Suzanne Eccles,  Florence Raynaud,  Wynne Aherne
Affiliations

Affiliation

  • 1 Chroma Therapeutics Ltd., Abingdon, OX14 4RY, UK. david.moffat@chromatherapeutics.com
PMID: 21080647 DOI: 10.1021/jm101177s
Abstract

A novel series of HDAC inhibitors demonstrating class I subtype selectivity and good oral bioavailability is described. The compounds are potent Enzyme inhibitors (IC₅₀ values less than 100 nM), and improved activity in cell proliferation assays was achieved by modulation of polar surface area (PSA) through the introduction of novel linking groups. Employing oral pharmacokinetic studies in mice, comparing drug levels in spleen to plasma, we selected compounds that were tested for efficacy in human tumor xenograft studies based on their potential to distribute into tumor. One compound, 21r (CHR-3996), showed good oral activity in these models, including dose-related activity in a LoVo xenograft. In addition 21r showed good activity in combination with other Anticancer agents in in vitro studies. On the basis of these results, 21r was nominated for clinical development.

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