Abstract:
:Histone Deacetylases (HDACs) have become important targets for the treatment of cancer and other diseases. In previous studies we described the development of novel spirocyclic HDAC inhibitors based on the combination of privileged structures with hydroxamic acid moieties as zinc binding group. Herein, we report further explorations, which resulted in the discovery of a new class of spiro[2H-(1,3)-benzoxazine-2,4'-piperidine] derivatives. Several compounds showed good potency of around 100 nM and less in the HDAC inhibition assays, submicromolar IC50 values when tested against tumour cell lines and a remarkable stability in human and mouse microsomes. Two representative examples exhibited a good pharmacokinetic profile with an oral bioavailability equal or higher than 35% and one of them studied in an HCT116 murine xenograft model showing a robust tumour growth inhibition. In addition, the two benzoxazines were found to have a minor affinity for the hERG potassium channel compared to their corresponding ketone analogues.
journal_name
Eur J Med Chemjournal_title
European journal of medicinal chemistryauthors
Thaler F,Varasi M,Abate A,Carenzi G,Colombo A,Bigogno C,Boggio R,Zuffo RD,Rapetti D,Resconi A,Regalia N,Vultaggio S,Dondio G,Gagliardi S,Minucci S,Mercurio Cdoi
10.1016/j.ejmech.2013.03.061subject
Has Abstractpub_date
2013-06-01 00:00:00pages
273-84eissn
0223-5234issn
1768-3254pii
S0223-5234(13)00221-3journal_volume
64pub_type
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