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SpringerBriefs in Pharmaceutical Science
& Drug Development

For further volumes:

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Arnab De

Application of Peptide-Based
Prodrug Chemistry in Drug
Development

With special thanks to Prof. Richard DiMarchi

(Standiford H. Cox Professor of Chemistry
and the Linda & Jack Gill Chair in Biomolecular
Sciences at Indiana University, Bloomington)

With foreword by Prof. Jean Martinez

(Legion d’Honneur and Chairman of
European Peptide Society, 2002–2010)

123
Arnab De
Hammer Health Sciences Center
Department of Microbiology
Columbia University Medical Center
New York, NY
USA

ISSN 1864-8118 ISSN 1864-8126 (electronic)

ISBN 978-1-4614-4874-7 ISBN 978-1-4614-4875-4 (eBook)
DOI 10.1007/978-1-4614-4875-4
Springer New York Heidelberg Dordrecht London

Library of Congress Control Number: 2012943626

Ó The Author(s) 2013

This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of
the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations,
recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or
information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar
methodology now known or hereafter developed. Exempted from this legal reservation are brief
excerpts in connection with reviews or scholarly analysis or material supplied specifically for the
purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the
work. Duplication of this publication or parts thereof is permitted only under the provisions of
the Copyright Law of the Publisher’s location, in its current version, and permission for use must always
be obtained from Springer. Permissions for use may be obtained through RightsLink at the Copyright
Clearance Center. Violations are liable to prosecution under the respective Copyright Law.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this
publication does not imply, even in the absence of a specific statement, that such names are exempt
from the relevant protective laws and regulations and therefore free for general use.
While the advice and information in this book are believed to be true and accurate at the date of
publication, neither the authors nor the editors nor the publisher can accept any legal responsibility for
any errors or omissions that may be made. The publisher makes no warranty, express or implied, with
respect to the material contained herein.

Printed on acid-free paper

Springer is part of Springer Science+Business Media (www.springer.com)

Foreword

Peptides are known to regulate most physiological processes, serving as endocrine

signals, neurotransmitters, or growth factors. Hence, they could be used thera-
peutically under diverse circumstances. Indeed, peptide-based drugs could poten-
tially be highly effective medicines and they are being increasingly used as drugs in
allergy, asthma, arthritis, cancer, diabetes, etc.
Traditionally, small molecules have been used in the pharmaceutical industry
by virtue of its oral availability, ability to cross membranes, and inexpensive
synthetic procedure. However, while the peptide is much larger and more
expensive to synthesize, it could be much more potent, specific, and pose fewer
side effects. However a major challenge in their therapeutic use is their relatively
short duration of action (measured in minutes). Thus, peptides represent a rich
natural source of potential medicines with one notable pharmaceutical limitation
being their relatively short duration of action.
A prototypical example of such a peptide is the endogenous hormone, gluca-
gon-like peptide-1 (GLP1) which has a physiological half-life of around 2 min.
Immediately after a meal, it stimulates the release of insulin, suppresses glucagon
levels, and delays gastric emptying. Since the insulinotropic action of GLP1 is
glucose-dependent, it acts only after a meal and not in the fasting state, thus
protecting against hypoglycemia. Multiple pharmaceutical companies are there-
fore exploring the possible use of GLP1 as therapy against diabetes. Longer acting
peptide agonists of the GLP1 receptor are also under clinical trial.
In this book, Arnab De, who is currently at Columbia University Medical Center,
provides insight into how prodrugs of peptides could be designed to improve the
pharmacodynamics of peptide drugs, synthetic procedures to make these prodrugs
and bioassays to examine the conversion of the prodrug into the drug under ther-
apeutic conditions. This book is partially inspired by the research conducted by him
at Indiana University, Bloomington. He presented this research at the American
Peptide Symposium 2009 in Bloomington and was awarded the Young Investiga-
tors’ Award. This volume provides examples of peptide-based prodrug chemistry
using GLP1 as a template. The author illustrates how to design prodrugs that slowly
convert to the parent drug at physiological conditions of 37 °C and pH 7.2 driven by

v
vi Foreword

their inherent chemical instability without the need for any enzymatic cleavage. I
recommend the book to the student community at large and especially to advanced
professionals in the field of pharmacy, medicinal chemistry, medicine, and bio-
chemistry. A detailed bibliography at the end will allow the readers to consult the
primary literature if required.

Prof. Jean Martinez

Chevalier of the Legion d’Honneur
Professor of Chemistry and Medicinal Chemistry,
Vice-Chairman of the Board of Governors of the
University of Montpellier, France
Director of Institut Des Biomolecules Max Mousseron
Chairman of European Peptide Society, 2002–2010
Preface

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 its short duration of action (half-life of 2 min 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. The 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 37 °C and pH 7.2
driven by their inherent chemical instability without the need for 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 use to chemists, biochemists, medicinal chemists, biolo-
gists, and people in the medical profession (doctors). It may be used in under-
graduate 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

vii
viii Preface

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).
Acknowledgments

I wish to convey my deepest regards for Prof. Richard DiMarchi at Indiana

University, Bloomington for his guidance in everything I do. I also thank Mr. Jay
Levy and Mr. David Smiley and Dr. Vasily Gelfanov for their valuable
suggestions.
I am also deeply grateful to Dr. Subho Mozumdar for his generous help in
different aspects of my life.
I take this opportunity to thank my parents (Dr. Arun Kumar De and Mrs.
Manjulika De) for my education, for helping me to imbibe the values that help to
get past challenging times. I thank my dear younger brother (Dr. Arka De) for
critically reading this manuscript. Finally, this book would not be written but for
the patient and invaluable feedback of my dear wife.
Thank you all!

ix
Contents

1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.1 Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.2 Insulin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
1.3 Glucagon-Likepeptide 1 (GLP 1). . . . . . . . . . . . . . . . . . . . . . . 5
1.4 Prodrug . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

2 Application of Prodrug Chemistry to GLP-1. . . . . . . . . . . . . . . . . 15

2.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

3 Experimental Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
3.1 Peptide Synthesis (Boc Amino Acids/HF Cleavage) . . . . . . . . . 24
3.2 Peptide Synthesis (Fmoc Amino Acids/HF Cleavage) . . . . . . . . 25
3.3 Depsipeptide Synthesis (Amino Ester Formation) . . . . . . . . . . . 25
3.4 N-Terminal Hydroxyl Peptide Synthesis
(a-Hydroxyl-N Terminal Extension). . . . . . . . . . . . . . . . . . . . . 26
3.5 HF Treatment of the Peptidyl-Resin. . . . . . . . . . . . . . . . . . . . . 27
3.6 Analysis Using Mass Spectrometry . . . . . . . . . . . . . . . . . . . . . 28
3.7 High Pressure Liquid Chromatography (HPLC) Analysis . . . . . . 28
3.8 Preparative Purification Using HPLC . . . . . . . . . . . . . . . . . . . . 29
3.9 Bioassay Experimental Design: Luciferase-Based
Reporter Gene Assay for cAMP Detection . . . . . . . . . . . ..... 29
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..... 29

4 Characterization of Prodrugs . . . . . . . . . ..... .............. 31

4.1 GLP-Oxyntomodulin . . . . . . . . . . . . ..... .............. 31
4.2 Adding Dipeptides to the N-Terminus ..... .............. 33
4.3 Adding Dipeptides to the N-Terminus of F7,
GLP(8-36)-CEX . . . . . . . . . . . . . . . ..... .............. 36

xi
xii Contents

4.4 Depsipeptides and Esters . . . .................... ..... 39

4.5 Adding Dipeptides to the OH Terminus of HO-F7,
GLP(8-36)-CEX . . . . . . . . . .................... ..... 39
4.6 Bioassays of Selected Longer Acting Prodrug Candidates ..... 50
References . . . . . . . . . . . . . . . . . .................... ..... 51

5 Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59

Appendix I: Schematic Synthesis of Longer Acting Prodrugs . . . . . . . 61

Appendix II: Structure of Peptides in Table A.1. . . . . . . . . . . . . . . . . 65

Appendix III: Structure of Peptides in Table A.2 . . . . . . . . . . . . . . . . 69

Appendix IV: Structure of Peptides in Table A.3 . . . . . . . . . . . . . . . . 71

Appendix V: Structure of Peptides in Table A.4 . . . . . . . . . . . . . . . . . 73

Appendix VI: Structure of Peptides in Table A.5 . . . . . . . . . . . . . . . . 75

Appendix VII: Structure of Peptides in Table A.6 . . . . . . . . . . . . . . . 79

Appendix VIII: Acylation of HO-His7, GLP(8–37) . . . . . . . . . . . . . . . 83

Appendix IX: A Note on Nomenclature . . . . . . . . . . . . . . . . . . . . . . . 87

About the Author . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89

Chapter 1
Introduction

Abstract This chapter introduces diabetes, an ancient disease that continues to

affect diverse populations in modern times and the various types of diabetes are
discussed. Insulin has been traditionally used to treat the disease. However, the one
significant limitation of using insulin is that an insulin overdose is the single most
potent cause of life-threatening hypoglycemia. Glucagon-like Peptide-1 (GLP1) is
a 30 amino acid peptide that stimulates insulin only when the blood glucose level
is high, hence the risk of hypoglycemia is substantially minimized. However, the
biggest problem in the therapeutic use of GLP-1 is its extremely short half-life in
plasma (*2 min). In the last subsection of this chapter, the utility of prodrugs is
discussed in general and how GLP-1 based prodrugs could appropriately extend
the biological half life and broaden the therapeutic index of GLP.

Keywords Diabetes Insulin
Glucagon-like Peptide-1
GLP-1
Prodrugs



Peptides Hypoglycemia

1.1 Diabetes

Diabetes is an ancient disease that continues to affect a diverse population in

modern times. The first recorded cases of diabetes date to ancient times in Egypt
and India (where it was called Madhumeha in ancient Ayurvedic medicine) [1].
The term ‘‘diabetes’’ was first coined by a Greek physician named Aretaeus of
Capasdocia [1].
The prevalence of diabetes has grown steadily over the last 30 years, largely as
a result of poor diet and a rapid rise in the prevalence of obesity. Diabetes is a
disease associated with sizable morbidity and excessive mortality. It imposes an
immense financial burden on those afflicted with the disease and general societal

A. De, Application of Peptide-Based Prodrug Chemistry in Drug Development, 1

SpringerBriefs in Pharmaceutical Science & Drug Development,
DOI: 10.1007/978-1-4614-4875-4_1, Ó The Author(s) 2013
2 1 Introduction

health care costs. It is broadly accepted that there currently is a worldwide

epidemic of Type 2 diabetes (often referred to as adult-onset diabetes). Moreover,
numerous clinical studies have shown that most cases could be prevented or
managed by lifestyle modifications and proper medication [2]. In certain demo-
graphic populations, like the Pima Indians of North America, as much as 30 % of
the adult population has been diagnosed with Type 2 diabetes. In the United States
alone, 18 million people (6.3 %) currently suffer from diabetes which in turn is a
leading cause of blindness and heart attacks, as well as kidney and vascular disease
[3, 4].
The primary physiological cause of diabetes is the defective utilization of
glucose by insulin-responsive cells in the body. Consequently, blood glucose
levels increase despite elevations in insulin concentrations and hyperglycemia
eventually emerges. The glucose accumulates in the blood instead of being
absorbed and metabolized. Therefore, the cells do not generate enough energy to
perform their normal activities while the persistently high blood glucose
concentration is damaging to numerous tissues, especially the eyes, kidney and
nerves.
There are three different forms of diabetes that are distinguished by their
etiological onset and progression. The physiological effects vary in severity and
cause, but all induce similar types of damage to physical health.
(1) Type 1 diabetes: Type 1 diabetes is often referred to as juvenile diabetes
because the majority of cases strike before adulthood. This is a chronic disease
of childhood and approximately 150,000 people under the age of 18 and more
than a million people in total are afflicted by this disease in the United States
alone. Its prevalence is rising at a rate of 3 % a year [5]. Over time, Type 1
diabetes can lead to serious medical complications such as cardiovascular
diseases, diabetic retinopathy and diabetic neuropathy [6]. Type 1 diabetes is
most often the result of a humoral based auto-immune response against b cells
of the islets of Langerhans which are located within the pancreas. These cells
are responsible for producing the insulin required for normal metabolic
homeostasis. Such patients typically lose about 80–90 % of their b cells [7]
and the remaining population is insufficient to meet the body’s normal insulin
requirements. This leads to hyperglycemia or what is also known as ‘‘insulin-
dependent diabetes’’. People diagnosed with Type 1 diabetes need to be
treated with daily insulin injections.
Type 1 diabetes also presents us with a challenging paradox. If the subjects
could be identified before hyperglycemia occurs, the initiation of the auto-
immune process might be prevented, thus halting the development of diabetes.
Unfortunately, a definitive diagnostic method to determine who will eventu-
ally develop Type 1 diabetes does not exist and attempts to develop such
methods would require large numbers of test subjects. Without such a diag-
nostic, the development of an efficacious therapy is difficult since finding the
subjects is very hard and the risk—benefit ratio of an experimental medicine in
a subject prior to disease onset is unknown [6].
1.1 Diabetes 3

(2) Type 2 diabetes (non insulin-dependent): This is the more common form of
diabetes. A healthy person’s body secretes enough insulin to maintain a steady
blood glucose level. In Type 2 diabetes, the body does not produce enough
insulin in a relative and often an absolute sense. Resistance to insulin action is
a physiological hallmark feature of this disease. This resistance to insulin is
often caused by obesity [8]. Although this is not a universal phenomenon,
underweight patients are often found to have had impaired insulin secretion
while the obese exhibit ‘‘insulin resistance’’ [9].
Approximately 90–95 % patients that suffer from diabetes reportedly have
Type 2 diabetes [10] which normally occurs after 40 years of age. Hence it is
known as ‘‘adult-onset diabetes’’. Due to changes in dietary habits and lack of
exercise, it is no longer uncommon for Type 2 diabetes to occur in younger
people, even adolescents. This shows a strong correlation with the alarming
rise in the prevalence of obesity and a sedentary lifestyle.
(3) Gestational diabetes: This occurs in pregnant women, hence the name. If the
blood glucose level is high in a woman during pregnancy but not at other times,
then she is said to have gestational diabetes. The cause is currently unknown but
seems similar to Type 2 diabetes where pregnancy imposes a level of insulin
resistance. Approximately 4 % of pregnant women are purported to have this
disease, and around 135,000 new cases are reported every year [11]. Further
observations show that approximately 50 % of gestational diabetes reappears as
Type 2 diabetes within 2 years of child bearing [11].

1.2 Insulin

In two landmark papers [12, 13] in 1922, Fredrick Banting, Charles Best, James
Collip and John Macleod reported the extraction of insulin from the pancreas of a
dog. This extract was subsequently shown to lower the blood glucose level in
surgically induced diabetic animal models. The clear demonstration that diabetes
is caused by the deficiency of insulin and could be reversed pharmacologically
makes these two of the more important scientific papers of the 20th century.
Insulin is a rather small protein, with a molecular weight of slightly less than
6,000 Daltons. The primary amino acid sequencing was accomplished by Sanger
in 1959 [14]. It is composed of two peptide chains, designated as the A chain and
B chain. The A chain has 21 amino acids while the B chain has 30.
The chains are linked by two disulfide bonds (residues A7 to B7, and A20 to
B19). In addition, there is a third intramolecular disulfide bond in the A chain
(residues A6 to A11) (Fig. 1.1). The complete conservation of these three disulfide
bonds throughout the mammalian phylum underscores the critical importance of
this bonding pattern. This also increases the structural complexity of the molecule
and makes it more difficult to synthesize as compared to a single peptide chain.
4 1 Introduction

G
I S
V
E S Chain A
Q
C C N
T S C
I C S L Y Q L E N Y T
F K
V S S P
N T
Q S
H Y
L S F
F
C
G S H R G
L V L V C G E
E A L Y
Chain B

Fig. 1.1 Primary structure of Insulin

Table 1.1 Pharmacodynamics of common insulin analogs

Onset Peak Actiona Durationa
(h) (h) (h)
HumalogÒ 0.25 0.5–1.5 3–5 (very fast)
Regular 0.5 2–4 6–8 (fast)
NPH, Lente 1–3 6–12 18–24 (slow)
Ultralente 4–8 12–18 24–28 (very slow)
a
Since patients respond to insulin differently, the peak action and duration are given as ranges

There are three important pharmacodynamic characteristics of a drug: its onset

(duration to biological action), its peak time (time at which the biological effect is
strongest), and finally its duration (sustained time of biological activity). There are
several unique forms of insulin designed to meet an individual patient’s daily
glucose demands (meal and fasting level). They are commonly classified into four
broad categories by their duration of action: very fast, fast, slow, and very slow
(Table 1.1).
The time action curves of some common insulin analogs are shown in Fig. 1.2.
Ultralente is a very slow acting insulin, hence it is usually used with HumalogÒ
(very fast acting) or native regular insulin (fast acting) [15] to more accurately
mimic the normal daily physiological variation in insulin activity.
Numerous combinations of these insulin analogs facilitate regulation of blood
glucose in virtually all forms of diabetes. However, they all have several severe
limitations. The most relevant is the finding that insulin overdose is the single most
potent cause of life-threatening hypoglycemia [16]. This has been confirmed by
many clinical trials, most notably by the Diabetes Control and Complications Trial
Research Group [17]. Studies performed in representative populations clearly
demonstrate that weight gain is another problem associated with insulin therapy
[18]. Such weight gain can paradoxically increase insulin resistance and thus the
amount of insulin needed. Obesity also increases cardiovascular risks [19].
While insulin is a miraculous substance it is a challenging medicine. Its com-
plex structure, especially its intra and intermolecular disulfide bonds makes it
difficult to synthesize in an inexpensive manner and the molecule hard to
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