Steroid acids derived from the biotransformation of the 17-ketol side- chain of corticosteroids have been identified in human and animal urine. The purpose of this investigation is to synthesize ester derivatives of steroid acids from potent corticosteroids and to evaluate the steroid as safer anti-inflammatory agents for prolonged use. The concept, antedrug, being formulated from the results of differences in anti-inflammatory potency of prototypes of the steroid acid derivatives depending on the routes of administration is that the derivatives possess anti- inflammatory activity per se, but upon entry into the circulatory system from the administration site, are hydrolyzed to inactive steroid acids. It is proposed to investigate the structure activity relationship, mechanism of action and pharmacokinetics of this new class of corticosteroids with metabolically labile group. New steroid acid esters will be synthesized and comprehensively evaluated as anti-inflammatory agents using the carrageenan-induced rat paw edema, croton oil-induced ear edema test and cotton pellet granuloma bioassay, with respect to various routes of administration. To further delineate the mode of action of the steroids, their effect on pituitary-adrenal function, glycogen deposition, and liberation of prostanoids and elastase will be studied. The metabolic rate of these steroids in rats will be investigated using radiolabeled compounds. Results of these studies will yield valuable insight into the structural characteristics for the maximum separation of local anti-inflammatory activity from systemic adverse effects and mode of action of these new corticosteroids with the promise of providing a solid rational basis for development of new potent anti-inflammatory steroids devoid of systemic side effects, which will therefore be more acceptable for use in the clinical environment.

Project Start
Project End
Budget Start
Budget End
Support Year
22
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Florida Agricultural and Mechanical University
Department
Type
DUNS #
City
Tallahassee
State
FL
Country
United States
Zip Code
32307
Johnston, Jermaine G; Pollock, David M (2018) Circadian regulation of renal function. Free Radic Biol Med 119:93-107
Adams, Mark K; Lee, Seung-Ah; Belyaeva, Olga V et al. (2017) Characterization of human short chain dehydrogenase/reductase SDR16C family members related to retinol dehydrogenase 10. Chem Biol Interact 276:88-94
Mochona, Bereket; Jackson, Timothy; McCauley, DeCoria et al. (2016) Synthesis and Cytotoxic Evaluation of Pyrrole Hetarylazoles Containing Benzimidazole/Pyrazolone/1,3,4-Oxadiazole Motifs. J Heterocycl Chem 53:1871-1877
Engel, Krysta L; French, Sarah L; Viktorovskaya, Olga V et al. (2015) Spt6 Is Essential for rRNA Synthesis by RNA Polymerase I. Mol Cell Biol 35:2321-31
Ayuk-Takem, Lambert; Amissah, Felix; Aguilar, Byron J et al. (2014) Inhibition of polyisoprenylated methylated protein methyl esterase by synthetic musks induces cell degeneration. Environ Toxicol 29:466-77
Chougule, Mahavir B; Patel, Apurva R; Patlolla, Ram et al. (2014) Epithelial transport of noscapine across cell monolayer and influence of absorption enhancers on in vitro permeation and bioavailability: implications for intestinal absorption. J Drug Target 22:498-508
Culpepper, Bonnie K; Webb, William M; Bonvallet, Paul P et al. (2014) Tunable delivery of bioactive peptides from hydroxyapatite biomaterials and allograft bone using variable-length polyglutamate domains. J Biomed Mater Res A 102:1008-16
Errahali, Younes J; Thomas, Leeshawn D; Keller 3rd, Thomas C S et al. (2013) Inhibition by new glucocorticoid antedrugs [16?, 17?-d] isoxazoline and [16?, 17?-d]-3'-hydroxy-iminoformyl isoxazoline derivatives of chemotaxis and CCL26, CCL11, IL-8, and RANTES secretion. J Interferon Cytokine Res 33:493-507
Stephenson, Adrienne P; Schneider, Jeffrey A; Nelson, Bryant C et al. (2013) Manganese-induced oxidative DNA damage in neuronal SH-SY5Y cells: attenuation of thymine base lesions by glutathione and N-acetylcysteine. Toxicol Lett 218:299-307
Godugu, Chandraiah; Patel, Apurva R; Doddapaneni, Ravi et al. (2013) Inhalation delivery of Telmisartan enhances intratumoral distribution of nanoparticles in lung cancer models. J Control Release 172:86-95

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