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.
|Titolo:||Spiro[chromane-2,4'-piperidine]-based histone deacetylase inhibitors with improved in vivo activity|
|Parole Chiave:||Molecular Structure; Administration, Oral; Animals; Blood Proteins; Injections, Intravenous; Antineoplastic Agents; Metabolic Clearance Rate; Mice, Nude; Mice; Cell Line, Tumor; Cell Proliferation; Structure-Activity Relationship; Piperidines; Half-Life; Cytochrome P-450 Enzyme System; Xenograft Model Antitumor Assays; Cell Cycle; Drug Evaluation, Preclinical; Histone Deacetylase Inhibitors|
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
Settore BIO/18 - Genetica
|Data di pubblicazione:||2012|
|Digital Object Identifier (DOI):||10.1002/cmdc.201200024|
|Appare nelle tipologie:||01 - Articolo su periodico|