Abstract:
:We evaluated the chemical and enzymatic stabilities of prodrugs containing methoxy, ethoxy and propylene glycol linkers in order to find a suitable linker for prodrugs of carboxylic acids with amino acids. l-Valine and l-phenylalanine prodrugs of model compounds (benzoic acid and phenyl acetic acid) containing methoxy, ethoxy and propylene glycol linkers were synthesized. The hydrolysis rate profile of each compound was studied at physiologically relevant pHs (1.2, 4, 6 and 7.4). Enzymatic hydrolysis of propylene glycol containing compounds was studied using Caco-2 homogenate as well as purified enzyme valacyclovirase. It was observed that the stability of the prodrugs increases with the linker length (propyl > ethyl > methyl). The model prodrugs were stable at acidic pH as compared to basic pH. It was observed that the prodrug with the aliphatic amino acid promoiety was more stable compared to its aromatic counterpart. The comparison between benzyl and the phenyl model compounds revealed that the amino acid side chain is significant in determining the stability of the prodrug whereas the benzyl or phenyl carboxylic acid had little or no effect on the stability. The enzymatic activation studies of propylene glycol linker prodrug in the presence of valacyclovirase and cell homogenate showed faster generation of the parent drug at pH 7.4. The half-life of prodrugs at pH 7.4 was more than 12 h, whereas in the presence of cell homogenate the half-lives were less than 1 h. Hydrolysis by Caco-2 homogenate generated the parent compound in two steps, where the prodrug was first converted to the intermediate, propylene glycol benzoate, which was then converted to the parent compound (benzoic acid). Enzymatic hydrolysis of propylene glycol containing prodrugs by valacyclovirase showed hydrolysis of the amino acid ester part to generate the propylene glycol ester of model compound (propylene glycol benzoate) as the major product. The amino acid prodrugs containing methoxy linker were the least stable while prodrugs containing propylene glycol linker were most stable. This work suggests that the propylene glycol linker is an optimal linker for amino acid prodrugs since it has good chemical stability and is enzymatically hydrolyzed to yield the parent drug. This approach can be further extended to other non-amino acid prodrugs and to provide a chemical handle to modify lead molecules containing carboxylic group(s).
journal_name
Mol Pharmjournal_title
Molecular pharmaceuticsauthors
Gupta D,Gupta SV,Lee KD,Amidon GLdoi
10.1021/mp900084vsubject
Has Abstractpub_date
2009-09-01 00:00:00pages
1604-11issue
5eissn
1543-8384issn
1543-8392journal_volume
6pub_type
杂志文章abstract::Ipratropium bromide, an anticholinergic drug used for the treatment of asthma and chronic obstructive pulmonary disease, has low oral bioavailability, but systemic exposure, superior to oral administration, can be achieved by inhalation. Therefore, we investigated the pulmonary absorption mechanism of ipratropium usin...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp900206j
更新日期:2010-02-01 00:00:00
abstract::sec-Butylpropylacetamide (SPD) is the amide derivative of valproic acid (VPA). SPD possess a wide-spectrum anticonvulsant profile better than that of VPA and blocks status epilepticus (SE) induced by pilocarpine and organophosphates. The activity of SPD on SE is better than that of benzodiazepines (BZDs) in terms of t...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.6b00221
更新日期:2016-07-05 00:00:00
abstract::A novel design of anticancer drug delivery system, based on an electrostatic binding of negatively charged liposomes and cationic metalloporphyrins under physiological conditions, is reported. A lack of cytotoxicity of the iron(III) porphyrin-loaded liposomes and an efficient generation of a toxic hydroxyl radical (OH...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp049936v
更新日期:2004-09-01 00:00:00
abstract::Process-induced phase transformations (PIPTs) of active pharmaceutical ingredients (APIs) can alter APIs' physicochemical properties and impact performance of pharmaceutical drug products. In this study, we investigated compression-induced amorphization of crystalline posaconazole (POSA), where the impact of mechanica...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.8b01122
更新日期:2019-02-04 00:00:00
abstract::Our previous studies have demonstrated that a generation 5 dendrimer (G5) conjugated with both folic acid (FA) and methotrexate (MTX) has a higher chemotherapeutic index than MTX alone. Despite this, batch-to-batch inconsistencies in the number of FA and MTX molecules linked to each dendrimer led to conjugate batches ...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp3002232
更新日期:2012-09-04 00:00:00
abstract::It is well established that polymers adopt a range of conformations and solution-state organization in response to varying solution environments, although very little work has been done to understand how these effects might impact the physical stability and bioavailability of spray-dried amorphous dispersions (SDDs). ...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.0c00729
更新日期:2020-12-07 00:00:00
abstract::The most promising F508del-CFTR corrector, VX-809, has been unsuccessful as an effective, stand-alone treatment for CF patients, but the rescue effect in combination with other drugs may confer an acceptable level of therapeutic benefit. Targeting cellular factors that modify trafficking may act to enhance the cell su...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.7b00928
更新日期:2018-03-05 00:00:00
abstract::Similar to glycolysis, glutaminolysis acts as a vital energy source in tumor cells, providing building blocks for the metabolic needs of tumor cells. To capture glutaminolysis in tumors, 18F-(2S,4R)4-fluoroglutamine ([18F]FGln) and 18F-fluoroboronoglutamine ([18F]FBQ) have been successfully developed for positron emis...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.9b00891
更新日期:2019-12-02 00:00:00
abstract::Combinatorial chemistry has enabled the production of very potent drugs that might otherwise suffer from poor solubility and low oral bioavailability. One approach to increase solubility is to make the drug amorphous, which leads to problems associated with drug stability. To improve stability, one option is to molecu...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp400712m
更新日期:2014-07-07 00:00:00
abstract::Recent studies on aqueous supersaturated lipophilic drug solutions prepared by methods including antisolvent addition, pH swing, or dissolution of amorphous solid dispersions (ASDs) have demonstrated that when crystallization is slow, these systems undergo liquid-liquid phase separation (LLPS) when the concentration o...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.6b00202
更新日期:2016-06-06 00:00:00
abstract::Bioadhesive nanoparticles based on poly(vinyl methyl ether/maleic anhydride) (PVMMA) and poly(ethylene glycol) methyl ether-b-poly(d,l-lactic acid) (mPEG-b-PLA) were produced by the emulsification solvent evaporation method. Paclitaxel was utilized as the model drug, with an encapsulation efficiency of up to 90.2 ± 4....
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.7b00612
更新日期:2017-10-02 00:00:00
abstract::While highly efficacious in treating rheumatoid arthritis (RA), the approved Janus kinase (JAK) inhibitor, Tofacitinib (Tofa, CP-690 550), has dose-dependent toxicities that limit its clinical application. In this study, we have examined whether a prodrug design that targets arthritic joints would enhance Tofa's thera...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.8b00433
更新日期:2018-08-06 00:00:00
abstract::Eight-armed PEG, molecular mass 10 kDa, was functionalized with furyl and maleimide groups, respectively; the obtained macromonomers were cross-linked via Diels-Alder chemistry. The mesh size (ξ) of the prepared hydrogels was determined by swelling studies, rheology, and low field NMR spectroscopy. The in vitro releas...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.5b00375
更新日期:2015-09-08 00:00:00
abstract::Achieving effective gene therapy for glioma depends on gene delivery systems. The gene delivery system should be able to cross the blood-brain barrier (BBB) and further target glioma at its early stage. Active brain tumor targeted delivery can be achieved using the "Trojan horse" technology, which involves either endo...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp500084s
更新日期:2014-10-06 00:00:00
abstract::Aerosol glucocorticoid medications have become more and more important in treating BA (bronchial asthma). Although these agents are dosed to directly target airway inflammation, adrenocortical suppression and other systematic effects are still seen. To tackle this problem in a novel way, two L-carnitine ester derivati...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp100412z
更新日期:2011-10-03 00:00:00
abstract::We examined the inhibitory effect of hydroxypropyl methylcellulose acetate succinate (HPMC-AS) on drug recrystallization from a supersaturated solution using carbamazepine (CBZ) and phenytoin (PHT) as model drugs. HPMC-AS HF grade (HF) inhibited the recrystallization of CBZ more strongly than that by HPMC-AS LF grade ...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp400278j
更新日期:2013-10-07 00:00:00
abstract::Penetratin is a classical cell-penetrating peptide with the potential to assist in the transmembrane delivery of proteins or drugs. However, the synthesis and application of cholesterol-penetratin (Chol-P) conjugates as nonviral delivery systems for microRNAs or drugs have not previously been reported. In this study, ...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.6b00211
更新日期:2016-07-05 00:00:00
abstract::Dissolution is a crucial process for the oral delivery of drug products. Before being absorbed through epithelial cell membranes to reach the systemic circulation, drugs must first dissolve in the human gastrointestinal (GI) tract. In vivo and in vitro dissolutions are complex because of their dependency upon the drug...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.0c00614
更新日期:2020-10-05 00:00:00
abstract::Myeloid differentiation primary response 88 (MyD88) is an intracellular adaptor protein central to the signaling of multiple receptors involved in inflammation. Since innate immune inflammation promotes autoimmunity, MyD88 is an attractive target in autoimmune disease. We previously developed c(MyD 4-4), a novel cycli...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.8b01180
更新日期:2019-04-01 00:00:00
abstract::Amphotericin B is a lifesaving polyene antibiotic used in the treatment of systemic mycoses. Unfortunately, the pharmacological applicability of this drug is limited because of its severe toxic side effects. At the same time, the lack of a well-defined mechanism of selectivity hampers the efforts to rationally design ...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.8b00572
更新日期:2018-09-04 00:00:00
abstract::Polymer therapeutics offer potential benefits in the treatment of multidrug resistant (MDR) infections; affording targeted delivery of biologically active agents to the site of inflammation, potential decreases in systemic toxicity, and the retention of antimicrobial activity at the target site. As a prototype model, ...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp500584u
更新日期:2014-12-01 00:00:00
abstract::This work demonstrates the way to achieve efficient and target specific delivery of a graphene quantum dot (GQD) using hyaluronic acid (HA) (GQD-HA) as a targeting agent. HA has been anchored to a GQD that accepts the fascinating adhesive properties of the catechol moiety, dopamine hydrochloride, conjugated to HA, whi...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp400219u
更新日期:2013-10-07 00:00:00
abstract::Structural features of lysine-conjugated antibody-drug conjugate (ADC) from humanized IgG1 were studied by small-angle X-ray scattering (SAXS). As the physicochemical properties of the cytotoxic drug (payload) and linker may impact the conformational and colloidal stabilities of the conjugated monoclonal antibody (mAb...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.9b00792
更新日期:2019-12-02 00:00:00
abstract::Recent developments in pharmaceutical technology have facilitated the design and production of modified release formulas for drugs whose physical, chemical or biological properties impede release and thus might compromise their efficacy or safety. One such drug is morphine, whose short half-life requires repeated dose...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp200019q
更新日期:2011-04-04 00:00:00
abstract::Metallacarborane moieties have been identified as promising pharmacophores. The pharmaceutical use of such compounds is, however, complicated by their low solubility and tendency to self-assemble in aqueous solution. In this work, we estimated the solubilities of a vast series of metallacarboranes [cobalt bis(dicarbol...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp300565z
更新日期:2013-05-06 00:00:00
abstract::Cell penetrating peptides (CPPs) have been extensively studied in polyelectrolyte complexes as a means to enhance the transfection efficiency of plasmid DNA (pDNA). Increasing the molecular weight of CPPs often enhances gene expression but poses a risk of increased cytotoxicity and immunogenicity compared to low molec...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp3007117
更新日期:2013-05-06 00:00:00
abstract::Some of the most significant therapeutic leads and agents used for the treatment of cancer target microtubule dynamics. Paclitaxel is an exceptional example that is currently used for treating a wide range of tumors. New, non-taxane microtubule stabilizers, including several epothilones, are advancing through clinical...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp060016h
更新日期:2006-07-01 00:00:00
abstract::Fexofenadine is a nonsedative antihistamine that exhibits good oral bioavailability despite its zwitterionic chemical structure and efflux by P-gp. Evidence exists that multiple uptake and efflux transporters play a role in hepatic disposition of fexofenadine. However, the roles of specific transporters and their inte...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp200026v
更新日期:2011-10-03 00:00:00
abstract::The Biopharmaceutical Classification System (BCS), which is a scientific approach to categorize active drug ingredient based on its solubility and intestinal permeability into one of the four classes, has been used to set the pharmaceutical quality standards for drug products in western society. However, it has receiv...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp300502m
更新日期:2013-05-06 00:00:00
abstract::Photodynamic therapy (PDT) has been shown to kill cancer cells and improve survival and quality of life in cancer patients, and numerous new approaches have been considered for maximizing the efficacy of PDT. In this study, a new multifunctional nanophotosensitizer Ce6/GE11-(pH)micelle was developed to target epiderma...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.7b00925
更新日期:2018-04-02 00:00:00