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

By Arnab De

Macromolecular (specifically peptide-based) medicines may possibly be powerful drugs. even though they've got a comparatively brief length of motion and variable healing index. An instance of this type of peptide is Glucagon-like Peptide I which may in all likelihood be used as a progressive drug for diabetes. it is because it stimulates insulin in basic terms while 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). besides the fact that it’s brief length of motion (half-life of two mins in plasma) precludes its healing use.

In this quantity, using novel therapeutics like GLP1 in its place to culture insulin-based medicines in diabetes is defined. Application of Peptide-Based Prodrug Chemistry in Drug Development elucidates the normal inspiration of prodrugs as “specialized non-toxic protecting teams utilized in a brief demeanour to change or to get rid of sure restricting houses within the guardian small molecule” (IUPAC definition). It is going directly to offer perception into how prodrugs of peptides (with GLP1 for instance) might be thoroughly used to increase the organic part existence, develop the healing index of macromolecules and enhance the pharmacodynamics of such medications. writer explains the common sense in the back of designing peptide prodrugs, artificial approaches and bioassays to check the conversion of the prodrug to the drug less than healing stipulations. The prodrugs defined slowly convert to the dad or mum drug at physiological stipulations of 37C and pH 7.2 pushed by way of their inherent chemical instability with no the necessity of any enzymatic cleavage. The diketopiperazine and diketomorpholine (DKP and DMP) recommendations for prodrug conversion are proven intimately with particular emphasis at the chemical flexibility that it bargains to boost prodrugs with variable time actions.

This publication might be of priceless tochemists, biochemists, medicinal chemists, biologists and folks within the scientific career (doctors). it can be utilized in undergraduate sessions yet will surely aid post-graduate scholars and complex pros.

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 college) for worthwhile feedback. The foreword for the booklet has been written via Prof. Jean Martinez, (Legion d'Honneur offered by means of the French Republic; Professor of Chemistry and Medicinal Chemistry of the collage of Montpellier, France; and Chairman of eu Peptide Society, 2002-2010).

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

Sample text

As before, dipeptides of differential tendency for intramolecular cyclization (diketopiperazine formation) and release of the parent drug (N-terminal hydroxyl peptide) were studied. While adding the dipeptide, both Class 3 (an amine nucleophile cleaving an ester bond) and Class 4 (a hydroxyl nucleophile cleaving an ester bond—Fig. 3) compounds were prepared and studied. The initial work began with imidazole-lactic acid (OH-His) as the terminal amino acid and subsequent leaving group. The HO-His7, GLP(8-37) was synthesized.

The HO-His7, GLP(8-37) was synthesized. It was a full agonist with 25 % the potency of native GLP-1. There were several attempts to add a dipeptide to the a hydroxyl group of HO-His7, GLP(8-37) and test for the cleavage of the new ester bond. However, there was a problem in selectively acylating the a-hydroxyl group of this peptide. As ‘‘protected’’ imidazole-lactic acid was not commercially available, we decided initially to work with the compound where the imidazole group was unprotected. As a result, the ‘‘unprotected imidazole’’ was inadvertently acylated along with the hydroxyl group.

Aliquots of 100 ll were drawn out at various time intervals, cooled to room temperature and analyzed by HPLC. The HPLC analyses were performed using a Beckman system gold chromatography system using a UV detector at 214 nm. 6 mm C18 Vydac column. The flow rate was 1 ml/min. 1 % TFA in 90 % CH3CN. A linear gradient was employed (40–70 % B in 15 min). The data was collected and analyzed using peak simple chromatography software. The initial rates of hydrolysis were used to measure the rate constant for the dissociation of the respective prodrugs.

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