ABSTRACT
The transcription factor STAT3 is a potential target for the treatment of castration-resistant prostate cancer. Galiellalactone (1), a direct inhibitor of STAT3, prevents the transcription of STAT3 regulated genes. In this study we characterized 6 (GPA512, Johansson , M. ; Sterner , O. Patent WO 2015/132396 A1, 2015 ), a prodrug of 1. In vitro studies showed that 6 is rapidly converted to 1 in plasma and is stable in a buffer solution. The pharmacokinetics of 6 following a single oral dose indicated that the prodrug was rapidly absorbed and converted to 1 with a tmax of 15 min. Oral administration of 6 in mice increased the plasma exposure of the active parent compound 20-fold compared to when 1 was dosed orally. 6 treated mice bearing DU145 xenograft tumors had significantly reduced tumor growth compared to untreated mice. The favorable druglike properties and safety profile of 6 warrant further studies of 6 for the treatment of castration-resistant prostate cancer.
Subject(s)
Acetylcysteine/analogs & derivatives , Antineoplastic Agents/pharmacology , Neoplasms, Experimental/pathology , Prodrugs/pharmacology , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathology , STAT3 Transcription Factor/antagonists & inhibitors , Acetylcysteine/chemical synthesis , Acetylcysteine/chemistry , Acetylcysteine/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Male , Mice , Mice, Nude , Models, Molecular , Molecular Structure , Neoplasms, Experimental/drug therapy , Prodrugs/chemical synthesis , Prodrugs/chemistry , STAT3 Transcription Factor/metabolism , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
Covalent inhibition is an efficient molecular mechanism for inhibiting enzymes or modulating the function of proteins and is found in the action of many drugs and biologically active natural products. However, it is has been less appreciated that the formation of covalent bonds can be reversible or irreversible. This review focuses on biologically active compounds that are Michael acceptors and how the reversible nature of the Michael addition reaction influences biological activity and how this can be exploited in designing prodrugs.
Subject(s)
Enzyme Inhibitors/chemistry , Prodrugs/chemistry , Drug Design , Enzyme Inhibitors/pharmacology , Humans , Prodrugs/pharmacologyABSTRACT
The synthesis and bronchorelaxing effects of a series of novel tetrahydroisoquinoline amides are described. The compounds were evaluated for their ability to relax LTD4 contracted isolated human small airways ex-vivo. Several compounds demonstrated highly efficacious bronchorelaxing properties. Cinnamide 71 was selected for further studies and constitutes a promising candidate as a novel bronchorelaxing agent for the treatment of pulmonary disorders.
