Chirality effect of C-20 on metabolism of methyl 11β,17α,20-trihydroxy-3-oxo-1,4-pregnadien-21-oate derivatives

Park, Kwan-Kyun; Ko, Dong-Hoon; You, Zhengqing; Cooperwood, John S.; Park, Jonghan; Lee, Henry Joung

doi:10.1016/j.steroids.2003.10.002

Cited by 4 publications

(15 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, the in vitro hydrolysis rates of steroidal anti-inflammatory antedrugs in rat or human blood plasma have been serving as very important criteria in antedrug study 28,67,71,72,75. The hydrolysis rates in most studies were expressed as half-life (t 1/2 ), which is the time it takes for 50% of the compounds to be hydrolyzed to inactive metabolites as determined by analytical HPLC.…”

Section: Pharmacology Of Anti-inflammatory Steroidal Antedrugsmentioning

confidence: 99%

“…Epimers at C20 of methyl 11 β , 17 α , 20-trihydroxy-3-oxo-1,4-pregnadiene-21-oates, their 9 α -fluoro analogs and their carbonate and acetonide derivatives ( 80 – 82 ) were subjected to similar in vitro hydrolysis rate study in rat plasma and liver homogenate 72. In rat plasma, the carboxy ester bonds of 20 β -triols and their acetonides were hydrolyzed remarkably faster (t 1/2 5.7 – 7.7 min) than their α -epimers (t 1/2 >2.5h) and those for the carbonate derivatives were even more profound with the t 1/2 of <1 min and ~3 min, respectively.…”

Section: Pharmacology Of Anti-inflammatory Steroidal Antedrugsmentioning

confidence: 99%

“…4). 71 The effect of increasing the size of the group at C16 was also examined by synthesizing 16α-malonyl and carboxymethyl compounds (e.g., 36 ), which showed reduced potency suggestive of a critical steric size requirement at this position 43…”

Section: Pharmacology Of Anti-inflammatory Steroidal Antedrugsmentioning

confidence: 99%

See 2 more Smart Citations

Synthesis and Pharmacology of Anti-Inflammatory Steroidal Antedrugs

Khan

Lee

2008

Chem. Rev.

View full text Add to dashboard Cite

Section: Pharmacology Of Anti-inflammatory Steroidal Antedrugsmentioning

confidence: 99%

Section: Pharmacology Of Anti-inflammatory Steroidal Antedrugsmentioning

confidence: 99%

See 1 more Smart Citation

Synthesis and Pharmacology of Anti-Inflammatory Steroidal Antedrugs

Khan

Lee

2008

Chem. Rev.

View full text Add to dashboard Cite

“…Epimers at C-20 of methyl 11β,17α,20-trihydroxy-3oxo-1,4-pregnadiene-21-oates, their 9α-fluoro analogs, their carbonate derivatives, and their acetonide derivatives (33)(34)(35) were subjected to similar in vitro hydrolysis rate study in rat plasma and liver homogenate by Lee et al [48]. In rat plasma, the carboxy ester bonds of 20β-triols and their acetonides were hydrolyzed remarkably faster (t 1/2 5.7 -7.7 min) than their α-epimers (t 1/2 >2.5h) and those for the carbonate derivatives were even more profound with the t 1/2 of <1 min and ~3 min, respectively.…”

Section: The Carboxylic Esters and Amidesmentioning

confidence: 99%

“…(7)) [12]. Thus, the in vitro hydrolysis rates of steroidal anti-inflammatory antedrugs in rat or human blood plasma have been serving as very important criteria in antedrug study [12,[46][47][48]57]. Even more remarkably the lactones were found stable in human lung S9 preparations while the ethyl esters were rapidly cleaved under the same conditions (Fig.…”

Section: -Butyrolactone Derivativesmentioning

confidence: 99%

Antedrugs: An Approach to Safer Drugs

Khan¹,

Park²,

Lee

2005

CMC

View full text Add to dashboard Cite

The antedrug concept was introduced by Lee and Soliman in 1982 in designing potent, yet safer locally active anti-inflammatory steroids. Antedrug is defined as an active synthetic derivative that is designed to undergo biotransformation to the readily excretable inactive form upon entry in the systemic circulation. Thus, are minimizing systemic side effects and are increasing the therapeutic indices. Steroid-21-oate esters have been developed as the first of this kind, which quickly hydrolyzed to the corresponding inactive steroid acids thereby exerting minimal systemic side effects. Later, other steroidal and nonsteroidal antedrugs have also been developed. The cost, complexity and length in development of a new therapeutic drug, in addition to the adverse drug reactions, the potential risk factors causing the withdrawal of the drugs from the market, have made the approach of antedrug design unique and attractive to the scientists involved in drug design. Considering these factors, the concept which strictly designed to eliminate the deleterious adverse systemic effects, is becoming an affordable approach in drug development arena. This review is not intended to be comprehensive; instead the focus will be on the recent advances in steroidal as well as nonsteroidal antedrugs, which appear to offer new leverage to the development of safer and more efficacious therapeutic agents.

show abstract

Synthesis and Biological Evaluation of 1,2,4-Triazinylphenylalkylthiazolecarboxylic Acid Esters as Cytokine-Inhibiting Antedrugs with Strong Bronchodilating Effects in an Animal Model of Asthma

et al. 2004

View full text Add to dashboard Cite

The influx of leukocytes (eosinophils, lymphocytes, and monocytes) into the airways and their production of proinflammatory cytokines contribute to the severity of allergic asthma. We describe here the synthesis and pharmacological evaluation of a series of triazinylphenylalkylthiazolecarboxylic acid esters that were designed to act as lung-specific antedrugs and inhibitors of the production of interleukin (IL)-5, a primary eosinophil-activating and proinflammatory cytokine. Closer examination of the hydroxypropyl ester, 15, indicated its high metabolic stability (t(1/2) > 240 min) in human lung S9 fraction but rapid conversion (t(1/2) = 15 min) into the pharmacologically inactive carboxylic acid by human liver preparations. In stimulated human whole blood cultures, 15 reduced not only the production of IL-5 (IC(50) = 78 nM) but also the biosynthesis of the monocyte chemotactic proteins MCP-1 (IC(50) = 220 nM), MCP-2 (IC(50) = 580 nM), and MCP-3 (IC(50) = 80 nM). In vivo, intratracheal administration of 15 (6 mg/animal) to allergic sheep, either before (-4 h) or after (+1.5 h) the pulmonary allergen challenge, completely abrogated the late-phase airway response and reduced the bronchial hyperreactivity to inhaled carbachol.

show abstract

Chirality effect of C-20 on metabolism of methyl 11β,17α,20-trihydroxy-3-oxo-1,4-pregnadien-21-oate derivatives

Cited by 4 publications

References 14 publications

Synthesis and Pharmacology of Anti-Inflammatory Steroidal Antedrugs

Synthesis and Pharmacology of Anti-Inflammatory Steroidal Antedrugs

Antedrugs: An Approach to Safer Drugs

Synthesis and Biological Evaluation of 1,2,4-Triazinylphenylalkylthiazolecarboxylic Acid Esters as Cytokine-Inhibiting Antedrugs with Strong Bronchodilating Effects in an Animal Model of Asthma

Contact Info

Product

Resources

About