PMEA Dotaz Zobrazit nápovědu
A simple HPLC/UV method for the determination of the transdermal permeation and dermal penetration of a broad-spectrum antiviral drug adefovir (PMEA) was developed. The separation was achieved on a C18 column with the mobile phase composed of 10 mM KH2PO4 and 2 mM Bu4NHSO4 at pH 6.0 and 7% acetonitrile. The method was validated with respect to selectivity, linearity (0.1-50 microg/ml), precision, accuracy, and stability. Transdermal permeation of 2% PMEA was studied in vitro using the Franz diffusion cell and porcine skin. The flux values were 1.8, 3.0, and 0.6 microg/cm2/h from aqueous donor samples at pH 3.4 and 7.4, and isopropyl myristate, respectively. The respective skin concentrations at 48 h were 294, 263, and 971 microg/g from these vehicles. These results will serve as a lead for further studies on transdermal and topical delivery of antivirals from the group of acyclic nucleoside phosphonates.
- MeSH
- adenin analogy a deriváty analýza aplikace a dávkování MeSH
- antivirové látky analýza aplikace a dávkování farmakokinetika MeSH
- aplikace kožní MeSH
- financování organizované MeSH
- kožní absorpce MeSH
- kůže metabolismus MeSH
- organofosfonáty analýza aplikace a dávkování farmakokinetika MeSH
- prasata MeSH
- reprodukovatelnost výsledků MeSH
- spektrofotometrie ultrafialová metody MeSH
- techniky in vitro MeSH
- vysokoúčinná kapalinová chromatografie metody MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
A series of 13 acyclic nucleoside phosphonates (ANPs) as bisamidate prodrugs was prepared. Five compounds were found to be non-cytotoxic and selective inhibitors of Bordetella pertussis adenylate cyclase toxin (ACT) in J774A.1 macrophage cell-based assays. The 8-aza-7-deazapurine derivative of adefovir (PMEA) was found to be the most potent ACT inhibitor in the series (IC50 =16 nm) with substantial selectivity over mammalian adenylate cyclases (mACs). AC inhibitory properties of the most potent analogues were confirmed by direct evaluation of the corresponding phosphonodiphosphates in cell-free assays and were found to be potent inhibitors of both ACT and edema factor (EF) from Bacillus anthracis (IC50 values ranging from 0.5 to 21 nm). Moreover, 7-halo-7-deazapurine analogues of PMEA were discovered to be potent and selective mammalian AC1 inhibitors (no inhibition of AC2 and AC5) with IC50 values ranging from 4.1 to 5.6 μm in HEK293 cell-based assays.
- MeSH
- adenin analogy a deriváty chemická syntéza chemie farmakologie MeSH
- adenylátcyklasy metabolismus MeSH
- Bacillus anthracis enzymologie MeSH
- Bordetella pertussis enzymologie MeSH
- inhibitory enzymů chemická syntéza chemie farmakologie MeSH
- molekulární struktura MeSH
- organofosfonáty chemická syntéza chemie farmakologie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- MeSH
- adenin analogy a deriváty farmakologie MeSH
- antitumorózní látky farmakologie MeSH
- antivirové látky farmakologie MeSH
- buněčné dělení účinky léků MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- lymfom T-buněčný farmakoterapie MeSH
- myši MeSH
- plíce cytologie MeSH
- slezina cytologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- myši MeSH
- zvířata MeSH
Novel small-molecule agents to treat Bordetella pertussis infections are highly desirable, as pertussis (whooping cough) remains a serious health threat worldwide. In this study, a series of 2-substituted derivatives of 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA, adefovir), in their isopropyl ester bis(L-phenylalanine) prodrug form, were designed and synthesized as potent inhibitors of adenylate cyclase toxin (ACT) isolated from B. pertussis. The series consists of PMEA analogues bearing either a linear or branched aliphatic chain or a heteroatom at the C2 position of the purine moiety. Compounds with a small C2 substituent showed high potency against ACT without cytotoxic effects as well as good selectivity over human adenylate cyclase isoforms AC1, AC2, and AC5. The most potent ACT inhibitor was found to be the bisamidate prodrug of the 2-fluoro PMEA derivative (IC50 =0.145 μM). Although the bisamidate prodrugs reported herein exhibit overall lower activity than the bis(pivaloyloxymethyl) prodrug (adefovir dipivoxil), their toxicity and plasma stability profiles are superior. Furthermore, the bisamidate prodrug was shown to be more stable in plasma than in macrophage homogenate, indicating that the free phosphonate can be effectively distributed to target tissues, such as the lungs. Thus, ACT inhibitors based on acyclic nucleoside phosphonates may represent a new strategy to treat whooping cough.
- MeSH
- adenin analogy a deriváty chemická syntéza chemie toxicita MeSH
- adenylátcyklasový toxin antagonisté a inhibitory metabolismus MeSH
- Bordetella pertussis metabolismus MeSH
- buněčné linie MeSH
- krysa rodu rattus MeSH
- léky antitumorózní - screeningové testy MeSH
- lidé MeSH
- myši MeSH
- organofosfonáty chemická syntéza chemie toxicita MeSH
- poločas MeSH
- potkani Wistar MeSH
- prekurzory léčiv chemie farmakokinetika toxicita MeSH
- protein - isoformy antagonisté a inhibitory metabolismus MeSH
- simulace molekulového dockingu MeSH
- terciární struktura proteinů MeSH
- vazba proteinů MeSH
- vazebná místa MeSH
- viabilita buněk účinky léků MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- adenin analogy a deriváty aplikace a dávkování terapeutické užití MeSH
- antitumorózní látky terapeutické užití MeSH
- antivirové látky terapeutické užití MeSH
- experimentální sarkom farmakoterapie chemicky indukované MeSH
- krysa rodu rattus MeSH
- myši MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- myši MeSH
- zvířata MeSH
- MeSH
- adenin analogy a deriváty aplikace a dávkování MeSH
- chromozomy účinky léků ultrastruktura MeSH
- inbrední kmeny potkanů genetika MeSH
- krysa rodu rattus MeSH
- lymfoidní leukemie farmakoterapie MeSH
- počet buněk genetika účinky léků MeSH
- transplantace nádorů metody MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
