Cyclosporin A prodrugs: design, synthesis and biophysical properties

Hamel, Arnaud; Hubler, Francis; Carrupt, A.; Wenger, Roland M.; Mutter, Manfred

doi:10.1111/j.1399-3011.2003.00111.x

Cited by 35 publications

(11 citation statements)

References 29 publications

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“…containing Aib or Sar) have been successfully employed in prodrugs of cytarabine [66] and cyclosporine A (CsA) [67]. Dipeptide esters of CsA thus obtained showed high thermodynamic stability, differential conversion rates under physiological conditions and strongly increased water solubility, offering a novel route for the design of CsA prodrugs [67].…”

mentioning

confidence: 99%

Cyclization-activated Prodrugs

2007

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Many drugs suffer from an extensive first-pass metabolism leading to drug inactivation and/or production of toxic metabolites, which makes them attractive targets for prodrug design. The classical prodrug approach, which involves enzyme-sensitive covalent linkage between the parent drug and a carrier moiety, is a well established strategy to overcome bioavailability/toxicity issues. However, the development of prodrugs that can regenerate the parent drug through non-enzymatic pathways has emerged as an alternative approach in which prodrug activation is not influenced by inter-and intraindividual variability that affects enzymatic activity. Cyclization-activated prodrugs have been capturing the attention of medicinal chemists since the middle-1980s, and reached maturity in prodrug design in the late 1990s. Many different strategies have been exploited in recent years concerning the development of intramoleculary-activated prodrugs spanning from analgesics to anti-HIV therapeutic agents. Intramolecular pathways have also a key role in two-step prodrug activation, where an initial enzymatic cleavage step is followed by a cyclization-elimination reaction that releases the active drug. This work is a brief overview of research on cyclization-activated prodrugs from the last two decades.

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confidence: 99%

Cyclization-activated Prodrugs

2007

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“…Consequently, we have replaced the N‐terminal amine with an α‐hydroxyl group and ester prodrugs were prepared at this site. Our intent is to cleave dipeptide‐ester extended GLP‐analogs through intramolecular cyclization with the formation of diketopiperzazine (DKP) or diketomorpholine (DMP) 16, 17. The intramolecular cyclization should generate the drug under physiological conditions (pH of 7.4 and 37°C) with first order kinetics.…”

Section: Introductionmentioning

confidence: 99%

“…There is appreciable precedent for the use of ester prodrugs in conventional drug design. Ester prodrugs of Floxuridine (FUdR)17 convert to active drug by general ester hydrolysis. The rate of hydrolysis was a function of structural considerations where the bulky substituents slowed the rate of hydrolysis of the FUdR prodrug.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and characterization of ester‐based prodrugs of glucagon‐like peptide 1

DiMarchi

2010

Biopolymers

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Peptides represent a rich natural source of potential medicines with one notable pharmaceutical limitation being their relatively short duration of action. A particularly good example of this phenomenon is glucagon-like peptide 1 (GLP), a hormone of appreciable interest for the treatment of type II diabetes. In the native form, GLP demonstrates an extremely short half-life in plasma and a relatively narrow therapeutic index with gastrointestinal adverse pharmacology. We envisioned a prodrug of GLP as a means to extend the duration of action and broaden the therapeutic index of this peptide hormone. We designed, synthesized, and characterized ester-based prodrugs of GLP that differentially convert to the parent drug under physiological conditions driven by their inherent chemical instability. In a set of dipeptide extended GLP-analogs we explored the rate of diketopiperazine (DKP) and diketomorpholine (DMP) formation, and the release of the active peptide. The rate of cleavage was observed to be a function of the conformation of the dipeptide promoiety and the strength of the cyclization nucleophile. Through the careful selection of chemical functionality, a set of GLP ester prodrugs of variable half-lives has been identified.

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“…The problem of the poor shelf-life stability of liposomal CsA formulations can be overcome via the preparation of a dry proliposome powder [55]. Cyclodextrins Improved bioavailability, reduced variability in absorption [80,81] Prodrugs High solubility in water, unknown pharmacokinetics [21,22] Brought to you by | MIT Libraries Authenticated Download Date | 5/12/18 5:24 AM Micelles composed of modified polysaccharides [64] are one of the promising alternative oral delivery vehicles. Their main advantage involves increasing the apical to basolateral permeability of CsA when compared to free CsA using a Caco-2 cell model.…”

Section: Systems For the Oral Delivery Of Cyclosporine Amentioning

confidence: 99%

“…For the same reason, improving solubility by salt formation is not feasible. To overcome these problems, soluble prodrugs have been designed which exhibit up to 25,000 times greater aqueous solubility and could be converted to CsA under physiological conditions [21,22]. However, these are still in the early stages of development.…”

Section: Introductionmentioning

confidence: 99%

Oral cyclosporine A - the current picture of its liposomal and other delivery systems

Czogalla¹

2009

Cellular and Molecular Biology Letters

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Abstract:The discovery of cyclosporine A was a milestone in organ transplantation and the treatment of autoimmune diseases. However, developing an efficient oral delivery system for this drug is complicated by its poor biopharmaceutical characteristics (low solubility and permeability) and the need to carefully monitor its levels in the blood. Current research is exploring various approaches, including those based on emulsions, microspheres, nanoparticles, and liposomes. Although progress has been made, none of the formulations is flawless. This review is a brief description of the main pharmaceutical systems and devices that have been described for the oral delivery of cyclosporine A in the context of the physicochemical properties of the drug and the character of its interactions with lipid membranes.

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Cyclosporin A prodrugs: design, synthesis and biophysical properties

Cited by 35 publications

References 29 publications

Cyclization-activated Prodrugs

Cyclization-activated Prodrugs

Synthesis and characterization of ester‐based prodrugs of glucagon‐like peptide 1

Oral cyclosporine A - the current picture of its liposomal and other delivery systems

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