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

• Published in: ChemMedChem 2012-04, Vol.7 (4), p.709-721
• Main Authors: Thaler, Florian, Varasi, Mario, Carenzi, Giacomo, Colombo, Andrea, Abate, Agnese, Bigogno, Chiara, Boggio, Roberto, Carrara, Simone, Cataudella, Tiziana, Dal Zuffo, Roberto, Reali, Veronica, Vultaggio, Stefania, Dondio, Giulio, Gagliardi, Stefania, Minucci, Saverio, Mercurio, Ciro
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; antiproliferation; Blood Proteins - metabolism; Cell Cycle - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Cytochrome P-450 Enzyme Inhibitors; Drug Evaluation, Preclinical; Half-Life; Histone Deacetylase Inhibitors - administration & dosage; Histone Deacetylase Inhibitors - chemistry; Histone Deacetylase Inhibitors - pharmacokinetics; Histone Deacetylase Inhibitors - pharmacology; histone deacetylases; hydroxamates; in vivo activity; Injections, Intravenous; Metabolic Clearance Rate; Mice; Mice, Nude; Molecular Structure; pharmacokinetics; Piperidines - chemistry; Structure-Activity Relationship; Xenograft Model Antitumor Assays
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201200024

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 in vitro antiproliferative activities, and in vitro ADME profiles. Based on these activities, 4‐fluorobenzyl and 2‐phenylethyl spirocycles were selected for further characterization. In vivo 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. Spiraling to new heights in HDAC inhibition: Herein we summarize the synthesis and biological evaluation of a series of spirochromane hydroxamic acid derivatives as novel inhibitors of human histone deacetylases. Selected compounds were studied for their in vivo pharmacokinetic behavior and for their antitumor activity in an HCT‐116 xenograft model.