A Novel Prodrug Strategy for β-Dicarbonyl Carbon Acids: Syntheses and Evaluation of the Physicochemical Characteristics of C-Phosphoryloxymethyl (POM) and Phosphoryloxymethyloxymethyl (POMOM) Prodrug Derivatives

Dhareshwar, S. S.; Stella, Valentino J.

doi:10.1002/jps.22021

Cited by 12 publications

(8 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the case of 4-hydroxytamoxifen, incorporation of the nucleotide element was desired to make this prodrug a substrate for a ribonuclease [27], a strategy designed to release a natural metabolite upon generation of the drug [26]. Variations of this approach have been employed with a number of other drugs [28–31] through functionalization of phenol substructures such as in prodrugs 15 – 17 [32], the nitrogen of phenyl hydantoins like derivatives 18 and 19 , and the relatively acidic carbon of β-dicarbonyl compounds [33]. While this appears to be an area of growing interest, in light of the recent review [32] it will not be considered in greater depth here.…”

Section: General Considerationsmentioning

confidence: 99%

Prodrugs of Phosphonates and Phosphates: Crossing the Membrane Barrier

Wiemer

2014

Topics in Current Chemistry

147

135

View full text Add to dashboard Cite

A substantial portion of metabolism involves transformation of phosphate esters, including pathways leading to nucleotides and oligonucleotides, carbohydrates, isoprenoids and steroids, and phosphorylated proteins. Because the natural substrates bear one or more negative charges, drugs that target these enzymes generally must be charged as well but small charged molecules can have difficulty traversing the cell membrane other than by endocytosis. The resulting dichotomy has stimulated abundant effort to develop effective prodrugs, compounds that carry little or no charge to enable them to transit biological membranes but then able to release the parent drug once inside the target cell. This chapter will present recent studies on advances in prodrug forms, along with representative examples of their application to marketed and developmental drugs.

show abstract

Section: General Considerationsmentioning

confidence: 99%

Prodrugs of Phosphonates and Phosphates: Crossing the Membrane Barrier

Wiemer

2014

Topics in Current Chemistry

147

135

View full text Add to dashboard Cite

show abstract

“…For instance, particle size reduction by milling 9 or micronization increases the specific surface area 10 ; modification of the structure of particles by increasing the amorphous fraction or modification of the polymorph type promote a faster dissolution 11 . The use of excipients such 690 E. Gundogdu 15 and chemical modification prodrugs also promote the dissolution of the drugs 16 .…”

Section: Introductionmentioning

confidence: 99%

Comparison of cefpodoxime proxetil release and antimicrobial activity from tablet formulations: Complexation with hydroxypropyl-β-cyclodextrin in the presence of water soluble polymer

Gündoğdu¹,

Köksal²,

Karasulu³

2011

Drug Development and Industrial Pharmacy

View full text Add to dashboard Cite

This study aims to prove the complexation of cefpodoxime proxetil (CP) by hydroxypropyl-β-cyclodextrin (HP-β-CD) in the presence of sodium carboxymethyl cellulose (Na CMC), and makes a comparison of commercial tablets by dissolution and antimicrobial activity studies. The CP--HP-β-CD complex was prepared by kneading method and characterized by SEM, FTIR and DSC. The solubility method was used to investigate the effect of HP-β-CD and Na CMC on the solubility of CP. The complex tablets were prepared using direct compression method. Dissolution studies were performed with complex tablets and commercial tablets in pH 1.2, 4.5, 6.8 and 7.4 buffer solutions. It was observed that complexation occurred in all formulations, and HP-β-CD is able to increase CP solubility and dissolution rate of CP was improved from complex tablets, when compared with commercial tablets. Furthermore, the antimicrobial activity studies revealed that the CP--HP-β-CD complex and complex tablets were shown to have more effective antimicrobial activity than commercial tablets. It is evident from the results that complexation with HP-β-CD in the presence of Na CMC is feasible way to prepare a more efficient tablet formulation with improved dissolution and antimicrobial activity.

show abstract

“…Incorporation of the phosphoryl-oxymethyl (POM) prodrug moiety has been an effective approach to improving aqueous solubility and oxidative stability of successful commercial products such as fosphenytoin and fospropofol (Stella, 1996;Stella and Nti-Addae, 2007;Dhareshwar and Stella, 2010). In vivo conversion of POM prodrugs to their active metabolites is mediated by phosphatases (Dhareshwar and Stella, 2008).…”

Section: Discussionmentioning

confidence: 99%

Preclinical Pharmacokinetics of Fosciclopirox, a Novel Treatment of Urothelial Cancers, in Rats and Dogs

Weir

Wood

Schorno

et al. 2019

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Pharmacokinetic studies in rats and dogs were performed to characterize the in vivo performance of a novel prodrug, fosciclopirox. Ciclopirox olamine (CPX-O) is a marketed topical antifungal agent with demonstrated in vitro and in vivo preclinical anticancer activity in several solid tumor and hematologic malignancies. The oral route of administration for CPX-O is not feasible due to low bioavailability and dose-limiting gastrointestinal toxicities. To enable parenteral administration, the phosphoryl-oxymethyl ester of ciclopirox (CPX), fosciclopirox (CPX-POM), was synthesized and formulated as an injectable drug product. In rats and dogs, intravenous CPX-POM is rapidly and completely metabolized to its active metabolite, CPX. The bioavailability of the active metabolite is complete following CPX-POM administration. CPX and its inactive metabolite, ciclopirox glucuronide (CPX-G), are excreted in urine, resulting in delivery of drug to the entire urinary tract. The absolute bioavailability of CPX following subcutaneous administration of CPX-POM is excellent in rats and dogs, demonstrating the feasibility of this route of administration. These studies confirmed the oral bioavailability of CPX-O is quite low in rats and dogs compared with intravenous CPX-POM. Given its broad-spectrum anticancer activity in several solid tumor and hematologic cancers and renal elimination, CPX-POM is being developed for the treatment of urothelial cancer. The safety, dose tolerance, pharmacokinetics, and pharmacodynamics of intravenous CPX-POM are currently being characterized in a United States multicenter first-inhuman Phase 1 clinical trial in patients with advanced solid tumors (NCT03348514).

show abstract

A Novel Prodrug Strategy for β-Dicarbonyl Carbon Acids: Syntheses and Evaluation of the Physicochemical Characteristics of C-Phosphoryloxymethyl (POM) and Phosphoryloxymethyloxymethyl (POMOM) Prodrug Derivatives

Cited by 12 publications

References 28 publications

Prodrugs of Phosphonates and Phosphates: Crossing the Membrane Barrier

Prodrugs of Phosphonates and Phosphates: Crossing the Membrane Barrier

Comparison of cefpodoxime proxetil release and antimicrobial activity from tablet formulations: Complexation with hydroxypropyl-β-cyclodextrin in the presence of water soluble polymer

Preclinical Pharmacokinetics of Fosciclopirox, a Novel Treatment of Urothelial Cancers, in Rats and Dogs

Contact Info

Product

Resources

About