ABSTRACT
N-(Pyridin-2-yl) arylsulfonamides 1 and 2 (PF-915275) were identified as potent inhibitors of 11ß-hydroxysteroid dehydrogenase type 1. A screen for bioactivation revealed that these compounds formed glutathione conjugates. This communication presents the results of a risk benefit analysis carried out to progress 2 (PF-915275) to a clinical study and the strategies used to eliminate reactive metabolites in this series of inhibitors. Based on the proposed mechanism of bioactivation and structure-activity relationships, design efforts led to N-(pyridin-2-yl) arylsulfonamides such as 18 and 20 that maintained potent 11ß-hydroxysteroid dehydrogenase type 1 activity, showed exquisite pharmacokinetic profiles, and were negative in the reactive metabolite assay.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Aminopyridines/pharmacokinetics , Sulfonamides/pharmacokinetics , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Aminopyridines/chemistry , Aminopyridines/pharmacology , Glutathione/pharmacokinetics , HEK293 Cells , Humans , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacologyABSTRACT
Polymeric prodrugs are one of the most promising chemotherapeutic agent delivery approaches, displaying unique drug release profiles, serum stability, formulation flexibility, and reduced drug resistance. One of the most important aspects of a polymeric prodrug, albeit a less-extensively studied one, is the polymer's molecular weight, which affects particle formation, drug release and PK/PD profiles, drug stability, and cell uptake; these factors in turn affect the prodrug's maximum tolerated dose and anticancer efficacy. Poly(L-γ-glutamylglutamine) (PGG) is a linear polymer designed to improve the therapeutic index of attached drugs. In this study we selected poly(L-γ-glutamylglutamine)-paclitaxel (PGGPTX), as a model system for the methodical investigation into the effects of the poly(L-γ-glutamylglutamine) backbone molecular weight on its pharmacological performance. The polymeric prodrug was characterized by NMR, DLS and GPC-MALS, and its anticancer activity in vitro and in vivo was assessed. Herein we present data which provide valuable insight into improving anticancer polymer-based prodrug design and development.
Subject(s)
Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Paclitaxel/analogs & derivatives , Proteins/chemistry , Proteins/therapeutic use , Animals , Antineoplastic Agents, Phytogenic/pharmacokinetics , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Cell Survival/drug effects , Female , Humans , Lung/drug effects , Lung/pathology , Lung Neoplasms/pathology , Mice , Mice, Nude , Molecular Weight , Neoplasms/drug therapy , Paclitaxel/chemistry , Paclitaxel/pharmacokinetics , Paclitaxel/therapeutic use , Prodrugs/chemistry , Prodrugs/pharmacokinetics , Prodrugs/therapeutic use , Proteins/pharmacokineticsABSTRACT
N-(Pyridin-2-yl) arylsulfonamides are identified as inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1), an enzyme that catalyzes the reduction of the glucocorticoid cortisone to cortisol. Dysregulation of glucocorticoids has been implicated in the pathogenesis of diabetes and the metabolic syndrome. In this Letter, we present the development of an initial lead to an efficient ligand with improved physiochemical properties using a deletion strategy. This strategy allowed for further optimization of potency leading to the discovery of the clinical candidate PF-915275.
