Spiro[chromane-2,4′-piperidine]-Based Histone Deacetylase Inhibitors with Improved invivo Activity

Florian Thaler, Mario Varasi, Giacomo Carenzi, Andrea Colombo, Agnese Abate, Chiara Bigogno, Roberto Boggio, Simone Carrara, Tiziana Cataudella, Roberto DalZuffo, Veronica Reali, Stefania Vultaggio, Giulio Dondio, Stefania Gagliardi, Saverio Minucci, Ciro Mercurio

Research output: Contribution to journalArticle

Abstract

A series of spiro[chromane-2,4′-piperidine] derivatives based on a previously published lead benzyl spirocycle 1 and bearing various N-aryl and N-alkylaryl substituents on the piperidine ring were prepared as novel histone deacetylase (HDAC) inhibitors. The compounds were evaluated for their abilities to inhibit nuclear HDACs, their invitro antiproliferative activities, and invitro ADME profiles. Based on these activities, 4-fluorobenzyl and 2-phenylethyl spirocycles were selected for further characterization. Invivo pharmacokinetic (PK) studies showed that both compounds exhibit an overall lower clearance rate, an increased half-life, and higher AUCs after intravenous and oral administration than spiropiperidine 1 under the conditions used. The improved PK behavior of these two compounds also correlated with superior in vivo antitumor activity in an HCT-116 xenograft model.

Original languageEnglish
Pages (from-to)709-721
Number of pages13
JournalChemMedChem
Volume7
Issue number4
DOIs
Publication statusPublished - Apr 2012

Keywords

  • Antiproliferation
  • Histone deacetylases
  • Hydroxamates
  • In vivo activity
  • Pharmacokinetics

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry
  • Molecular Medicine

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  • Cite this

    Thaler, F., Varasi, M., Carenzi, G., Colombo, A., Abate, A., Bigogno, C., Boggio, R., Carrara, S., Cataudella, T., DalZuffo, R., Reali, V., Vultaggio, S., Dondio, G., Gagliardi, S., Minucci, S., & Mercurio, C. (2012). Spiro[chromane-2,4′-piperidine]-Based Histone Deacetylase Inhibitors with Improved invivo Activity. ChemMedChem, 7(4), 709-721. https://doi.org/10.1002/cmdc.201200024