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 usefulto 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).
