Read e-book online Application of Peptide-Based Prodrug Chemistry in Drug PDF

By Arnab De

ISBN-10: 1461448743

ISBN-13: 9781461448747

ISBN-10: 1461448751

ISBN-13: 9781461448754

Macromolecular (specifically peptide-based) medications may most likely be powerful medications. notwithstanding they've got a comparatively brief period of motion and variable healing index. An instance of this kind of peptide is Glucagon-like Peptide I that could in all probability be used as a progressive drug for diabetes. for the reason that it stimulates insulin in simple terms whilst the blood glucose point is excessive thereby decreasing the chance of hypoglycemia (a major drawback of utilizing insulin is that an insulin overdose is the only such a lot effective reason for life-threatening hypoglycemia). in spite of the fact that it’s brief period of motion (half-life of two mins in plasma) precludes its healing use.

In this quantity, using novel therapeutics like GLP1 as a substitute to culture insulin-based medications in diabetes is defined. Application of Peptide-Based Prodrug Chemistry in Drug Development elucidates the normal suggestion of prodrugs as “specialized non-toxic protecting teams utilized in a temporary demeanour to change or to put off sure restricting houses within the mum or dad small molecule” (IUPAC definition). It is going directly to offer perception into how prodrugs of peptides (with GLP1 to illustrate) can be accurately used to increase the organic part existence, increase the healing index of macromolecules and enhance the pharmacodynamics of such medications. writer explains the common sense in the back of designing peptide prodrugs, man made strategies and bioassays to ascertain the conversion of the prodrug to the drug less than healing stipulations. The prodrugs defined slowly convert to the mum or dad drug at physiological stipulations of 37C and pH 7.2 pushed via their inherent chemical instability with no the necessity of any enzymatic cleavage. The diketopiperazine and diketomorpholine (DKP and DMP) recommendations for prodrug conversion are established intimately with exact emphasis at the chemical flexibility that it deals to strengthen prodrugs with variable time actions.

This publication could be of valuable tochemists, biochemists, medicinal chemists, biologists and other people within the clinical occupation (doctors). it can be utilized in undergraduate sessions yet will surely support post-graduate scholars and complicated execs.

The writer is thankful to Prof. Richard DiMarchi (Standiford H. Cox Professor of Chemistry and the Linda & Jack Gill Chair in Biomolecular Sciences at Indiana collage) for useful feedback. The foreword for the ebook has been written by way of Prof. Jean Martinez, (Legion d'Honneur provided through the French Republic; Professor of Chemistry and Medicinal Chemistry of the collage of Montpellier, France; and Chairman of ecu Peptide Society, 2002-2010).

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Extra info for Application of Peptide-Based Prodrug Chemistry in Drug Development

Example text

All these esters, including #3 cleaved at 100 °C. In all these cases, there is HO-Phe in the first position (hydroxy phenylalanyl leaving group) of GLP 44 4 Characterization of Prodrugs CH2Ph CH2Ph O CH O H X GLP (8-36) CEX X H 6 NH 5 O O CH O OH GLP (8-36) CEX 6 NH OH 5 O H CH2Ph 1 H CH2Ph 2 1: L,L-dipeptide extension 2: L,D-dipeptide extension CH2Ph O CH O H GLP (8-36) CEX 6 NH 5 O NH2 H CH2Ph Fig. 8 a HO-F5X6-O-F7, GLP(8-36)-CEX structures. 1: L,L-dipeptide extension; 2: dipeptide extension.

The degradation half lives of the respective prodrugs were calculated based on the first-order kinetics (t1/2 = 693/k) where ‘k’ is the first-order rate constant for the degradation of the prodrug. The disappearance of the prodrug and the appearance of the drug were both simultaneously analysed and calculated using HPLC. Generally, there was an excellent mass balance between the loss of the prodrug and the appearance of the drug. However in our results, only the estimated half life of the disappearance of the prodrug has been reported.

The initial rates of hydrolysis were used to measure the rate constant for the dissociation of the respective prodrugs. The concentrations of the prodrug and the drug were estimated from their peak areas respectively. The first-order dissociation rate constants of the prodrugs were determined by plotting the logarithm of the concentration of the prodrug at various time intervals. The slope of this plot gives the rate constant ‘k’. 693/k. 8 Preparative Purification Using HPLC After we were satisfied that the prodrug had an appropriate t1/2, the prodrug was purified.

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Application of Peptide-Based Prodrug Chemistry in Drug Development by Arnab De


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