title: Spiro[chromane-2,4'-piperidine]-based histone deacetylase inhibitors with improved in vivo activity.
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 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.
authors.affiliation: Genextra Group, Congenia s.r.l., Via Adamello 16, 20139 Milan, Italy.florian.thaler@ifom-ieo-campus.it
authors.forename: Florian
authors.initials: F
authors.lastname: Thaler
authors.forename: Mario
authors.initials: M
authors.lastname: Varasi
authors.forename: Giacomo
authors.initials: G
authors.lastname: Carenzi
authors.forename: Andrea
authors.initials: A
authors.lastname: Colombo
authors.forename: Agnese
authors.initials: A
authors.lastname: Abate
authors.forename: Chiara
authors.initials: C
authors.lastname: Bigogno
authors.forename: Roberto
authors.initials: R
authors.lastname: Boggio
authors.forename: Simone
authors.initials: S
authors.lastname: Carrara
authors.forename: Tiziana
authors.initials: T
authors.lastname: Cataudella
authors.forename: Roberto
authors.initials: R
authors.lastname: Dal Zuffo
authors.forename: Veronica
authors.initials: V
authors.lastname: Reali
authors.forename: Stefania
authors.initials: S
authors.lastname: Vultaggio
authors.forename: Giulio
authors.initials: G
authors.lastname: Dondio
authors.forename: Stefania
authors.initials: S
authors.lastname: Gagliardi
authors.forename: Saverio
authors.initials: S
authors.lastname: Minucci
authors.forename: Ciro
authors.initials: C
authors.lastname: Mercurio
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001798:Blood Proteins / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D065607:Cytochrome P-450 Enzyme Inhibitors; D004353:Drug Evaluation, Preclinical; D006207:Half-Life; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D007275:Injections, Intravenous; D008657:Metabolic Clearance Rate; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D010880:Piperidines / Q000737:chemistry*; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001798:Blood Proteins; D065607:Cytochrome P-450 Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D010880:Piperidines