Macromolecular (specifically peptide-based) drugs could potentially be
highly effective medicines. However they have a relatively short
duration of action and variable therapeutic index. An example of such a
peptide is Glucagon-like Peptide I which could potentially be used as a
revolutionary drug for diabetes. This is because it stimulates insulin
only when the blood glucose level is high thereby reducing the risk of
hypoglycemia (a significant disadvantage of using insulin is that an
insulin overdose is the single most potent cause of life-threatening
hypoglycemia). However it's short duration of action (half-life of 2
minutes in plasma) precludes its therapeutic use.
In this volume, the use of novel therapeutics like GLP1 as an
alternative to tradition insulin-based drugs in diabetes is described.
Application of Peptide-Based Prodrug Chemistry in Drug Development
elucidates the traditional concept of prodrugs as "specialized non-toxic
protective groups used in a transient manner to alter or to eliminate
certain limiting properties in the parent small molecule" (IUPAC
definition). It goes on to provide insight into how prodrugs of peptides
(with GLP1 as an example) could be appropriately used to extend the
biological half life, broaden the therapeutic index of macromolecules
and improve the pharmacodynamics of such drugs. Author explains the
logic behind designing peptide prodrugs, synthetic procedures and
bioassays to examine the conversion of the prodrug to the drug under
therapeutic conditions. The prodrugs described slowly convert to the
parent drug at physiological conditions of 37C and pH 7.2 driven by
their inherent chemical instability without the need of any enzymatic
cleavage. The diketopiperazine and diketomorpholine (DKP and DMP)
strategies for prodrug conversion are demonstrated in detail with
special emphasis on the chemical flexibility that it offers to develop
prodrugs with variable time actions.
This book will be of useful to chemists, biochemists, medicinal
chemists, biologists and people in the medical profession (doctors). It
may be used in undergraduate classes but will certainly help
post-graduate students and advanced professionals.
The author is grateful to Prof. Richard DiMarchi (Standiford H. Cox
Professor of Chemistry and the Linda & Jack Gill Chair in Biomolecular
Sciences at Indiana University) for valuable suggestions. The foreword
for the book has been written by Prof. Jean Martinez, (Legion d'Honneur
awarded by the French Republic; Professor of Chemistry and Medicinal
Chemistry of the University of Montpellier, France; and Chairman of
European Peptide Society, 2002-2010).
