Current
Topics in Medicinal Chemistry
ISSN: 1568-0266
Current Topics
in Medicinal Chemistry
Volume 7, Number 6, 2007
Contents
DPP-IV as a Target in Medicinal Chemistry
and Drug Discovery
Guest Editor: Dr. Jens-Uwe Peters
Editorial Pp. 545
Dipeptidyl Peptidase IV Inhibitors:
The Next Generation of New Promising Therapies for the Management
of Type 2 Diabetes Pp. 547-555
Elena Sebokova, Andreas D. Christ, Markus Boehringer and
Jacques Mizrahi
[Abstract]
Discovery of JANUVIA™ (Sitagliptin), a Selective
Dipeptidyl Peptidase IV Inhibitor for the Treatment of Type2
Diabetes Pp. 557-568
Nancy A. Thornberry and Ann E. Weber
[Abstract]
Aromatic Heterocycle-Based DPP-IV Inhibitors: Xanthines
and Related Structural Types Pp. 569-578
Bruce G. Szczepankiewicz and Ravi Kurukulasuriya
[Abstract]
11 Years of Cyanopyrrolidines as DPP-IV Inhibitors
Pp. 579-595
Jens-Uwe Peters
[Abstract]
Azetidine-Based Inhibitors of Dipeptidyl Peptidase
IV (DPP IV) Pp. 597-608
Dana Ferraris, Sergei Belyakov, Weixing Li, Eddie Oliver,
Yao Sen Ko, David Calvin, Susan Lautar, Bert Thomas and Camilo
Rojas
[Abstract]
Molecular Recognition of Ligands in Dipeptidyl Peptidase
IV Pp. 609-619
Bernd Kuhn, Michael Hennig, and Patrizio Mattei
[Abstract]
Prolyl Peptidases Related to Dipeptidyl Peptidase
IV: Potential of Specific Inhibitors in Drug Discovery
Pp. 621-635
Pieter Van der Veken, Achiel Haemers and Koen Augustyns
[Abstract]
Molecule
of Month
Abstracts
[Back to top]
Editorial
The serine protease DPP-IV (dipeptidyl peptidase IV, DP
IV) has been a subject of research since its discovery in
1967. The role of this enzyme in glucose homeostasis was elucidated
in the 1990s, and DPP-IV inhibition was recognized as a potential
treatment of type 2 diabetes with anticipated advantages over
established therapies. This led to an immense increase in
research, and has made this enzyme one of the most popular
therapeutic targets of the last ten years. In April 2006,
five DPP-IV inhibitors had reached phase III clinical trials,
and New Drug Applications had been filed for two of them.
Today, we can hope to have DPP-IV inhibitors available as
novel treatments for type 2 diabetes in the near future. This
issue aims to document the discoveries of some of these new
medicines, and the current status of research.
The issue is opened by Elena Sebokova, Andreas D. Christ,
Markus Böhringer and Jacques Mizrahi, who give an introduction
to the biological background of DPP-IV and the incretin system,
and summarise the current knowledge on DPP-IV as a target
for type 2 diabetes. The authors interpret salient preclinical
results and clinical studies and discuss why DPP-IV inhibitors
have the potential to become the next generation of antidiabetic
drugs.
The next reviews focus on some of the most prominent series
of DPP-IV inhibitors.
In their story of the β-phenethylamines,
Nancy A. Thornberry and Ann E. Weber give an account of the
research that led to the discovery of one of the most advanced
DPP-IV inhibitors, sitagliptin. This case study is full of
elegant solutions to a variety of encountered issues and will
certainly become a classic!
Bruce Szczepankiewicz and Ravi Kurukulasuriya give an insightful
overview on the xanthine-type DPP-IV inhibitors. The xanthines
are a diverse class of inhibitors and have so far been described
mainly in patent literature. A xanthine-derived compound,
SYR322, is currently undergoing phase III clinical trials.
This is followed by a review on another popular compound class,
the cyanopyrrolidines. The evolution of different subseries,
which cumulated in the discoveries of vildagliptin and saxagliptin,
is described.
These reviews on major series of DPP-IV inhibitors are complemented
by highlighting a particular series in the wide field of peptide-like
inhibitors, the azetidines. A team of authors around Dana
Ferraris, who has been a key player in the exploration of
the azetidines, introduces us to the details of this compound
class.
X-ray crystal structures have revealed that all these inhibitors
share common key interactions in their recognition by DPP-IV.
Bernd Kuhn, Michael Hennig, and Patrizio Mattei review the
molecular recognition by DPP-IV in detail. The authors combine
structural information with published SAR data to explain
the characteristics of DPP-IV’s recognition sites, and
discuss possibilities for structure-based design and virtual
screening.
Throughout this issue, DPP-IV related enzymes like FAP, DPP8,
DPP9, and DPP-II are repeatingly mentioned. These „DASH
proteins“ are reviewed in a final contribution to this
issue by Pieter Van der Veken, Achiel Haemers, and Koen Augustyns.
The function and significance of these enzymes, as well as
their properties and the SAR of their inhibitors, are extensively
discussed. Interestingly, some of these enzymes are promising
therapeutic targets on their own.
Thanks to all authors, this issue has become a collection
of inspiring contributions to a range of DPP-IV related topics.
Hopefully anyone engaged in the field of DPP-IV, antidiabetics,
proteases, or with an interest in drug discovery in general,
will enjoy it!
Dr. Jens-Uwe Peters
F. Hoffmann-La Roche Ltd.
Discovery Chemistry
CH-4070 Basel,
Switzerland
jens-uwe.peters@roche.com
[Back to top]
Dipeptidyl Peptidase IV Inhibitors: The Next Generation
of New Promising Therapies for the Management of Type 2 Diabetes
Elena Sebokova, Andreas D. Christ, Markus Boehringer and
Jacques Mizrahi
Type 2 diabetes is a chronic metabolic disease characterized
by the presence of both fasting and postprandial hyperglycemia
which is a result of pancreas β-cell
dysfunction, deficiency in insulin secretion, insulin resistance
and/or increased hepatic glucose production. More recently,
the role of other glucoregulatory hormones, including glucagon,
amylin, and the gut peptide glucagon-like peptide (GLP)-1,
and an increase in the rate of postmeal carbohydrate absorption
have also been included as important pathophysiologic defects.
Existing anti-diabetes medications are often unefficient at
achieving sustained glycemic control because they predominantly
address only a single underlying defect. A number of alternative
therapies for type 2 diabetes are currently under development
that take advantage of the actions of the incretin hormones
glucagon-like peptide-1 and glucose-dependent insulinotropic
polypeptide on the pancreatic β-cell.
One such approach is based on the inhibition of dipeptidyl
peptidase IV (DPP-IV), the major enzyme responsible for degrading
the incretins in vivo. DPP-IV exhibits characteristics
that have allowed the development of specific inhibitors with
proven efficacy in improving glucose tolerance in animal models
of diabetes and type 2 diabetic patients. While enhancement
of insulin secretion, resulting from blockade of incretin
degradation, has been proposed to be the major mode of inhibitor
action, there is also evidence that inhibition of gastric
emptying, reduction in glucagon secretion, peripheral insulin
sensitization and important effects on β-cell
differentiation and survival can potentially preserve β-cell
mass, and improve insulin secretory function and glucose handling
in diabetic patients. The present article focuses on the preclinical
and clinical data of DPP-IV inhibitors that make it unique
therapeutic agents representing the next generation of antidiabetes
drugs.
[Back to top]
Discovery of JANUVIA™ (Sitagliptin), a Selective
Dipeptidyl Peptidase IV Inhibitor for the Treatment of Type2
Diabetes
Nancy A. Thornberry and Ann E. Weber
The emergence of glucagon-like peptide 1 (GLP-1) as a well
validated approach to the treatment of type 2 diabetes and
preclinical validation of dipeptidyl peptidase IV (DPP-4)
inhibition as an alternate, oral approach to GLP-1 therapy
prompted the initiation of a DPP-4 inhibitor program at Merck
in 1999. DPP-4 inhibitors threo- and allo-isoleucyl
thiazolidide were in-licensed to jump start the program; however,
development was discontinued due to profound toxicity in rat
and dog safety studies. The observation that both compounds
inhibit the related proline peptidases DPP8 and DPP9 led to
the hypothesis that inhibition of DPP8 and/or DPP9 could evoke
severe toxicities in preclinical species. Indeed, the observed
toxicities were recapitulated with a selective dual DPP8/9
inhibitor but not with an inhibitor selective for DPP-4. Thus,
medicinal chemistry efforts focused on identifying a highly
selective DPP-4 inibitor for clinical development. Initial
work in an α-amino
acid series related to isoleucyl thiazolidide was discontinued
due to lack of selectivity; however, SAR studies on two screening
leads led to the identification of a highly selective β-amino
acid piperazine series. In an effort to stabilize the piperazine
moiety, which was extensively metabolized in vivo,
a series of bicyclic derivatives were prepared, culminating
in the identification of a potent and selective triazolopiperazine
series. Unlike their monocyclic counterparts, these analogs
typically showed excellent pharmacokinetic properties in preclinical
species. Optimization of this series led to the discovery
of JANUVIA™ (sitagliptin), a highly selective DPP-4
inhibitor for the treatment of type 2 diabetes.
[Back to top]
Aromatic Heterocycle-Based DPP-IV Inhibitors: Xanthines
and Related Structural Types
Bruce G. Szczepankiewicz and Ravi Kurukulasuriya
Xanthines and xanthine-like DPP-IV inhibitors were first disclosed
in 2002. Since then, several dozen accounts of xanthine-based
DPP-IV inhibitors have been published. Only a few presentations
and journal articles have appeared, with the vast majority
of information coming from the patent literature. DPP-IV inhibitors
related to the xanthines include purine analogues with other
arrangements of the nitrogen atoms in the core structure,
imidazoles, uracils, pyrimidines, pyridines, and some fused
pyridines. At least one compound derived from the xanthines
has advanced into clinical trials, making it likely that these
molecules will play a major role in the DPP-IV inhibition
arena over the next several years.
[Back to top]
11 Years of Cyanopyrrolidines as DPP-IV Inhibitors
Jens-Uwe Peters
Cyanopyrrolidines (cyanopyrrolidides, pyrrolidine-2-nitriles,
prolinenitriles) as inhibitors of the serine protease dipeptidyl
peptidase IV (DPP-IV, DP IV, CD26, EC 3.4.14.5) were first
reported in 1995. The interest in this compound class grew
immensely when DPP-IV was discovered as a target for the treatment
of type 2 diabetes. The research on cyanopyrrolidines cumulated
in the discoveries of vildagliptin (LAF237, NVP-LAF237) and
saxagliptin (BMS-477118). These compounds entered Phase III
clinical trials in 2004 and 2005, respectively, and an application
for market approval has been filed for vildagliptin in 2006.
Today cyanopyrrolidines are, as judged by the numbers of patent
applications, the most prominent of several series of DPP-IV
inhibitors, and have the potential to become valuable medicines
for type 2 diabetes in the near future. This review summarizes
some historical aspects of the discovery of cyanopyrrolidine
DPP-IV inhibitors, and then focuses mainly on structure-activity-relationships,
the evolution of different subseries, the possibilities to
improve on the chemical instability that is associated with
this compound class, and on the discoveries of vildagliptin
and saxagliptin. Within this context, the properties of individual
compounds and results from biological studies are discussed.
The rationale of DPP-IV inhibition, clinical data, and the
relevance of selectivity over related proteases are extensively
reviewed in other contributions to this issue of Curr.
Top. Med. Chem., and are therefore only very briefly
touched.
[Back to top]
Azetidine-Based Inhibitors of Dipeptidyl Peptidase
IV (DPP IV)
Dana Ferraris, Sergei Belyakov, Weixing Li, Eddie Oliver,
Yao Sen Ko, David Calvin, Susan Lautar, Bert Thomas and Camilo
Rojas
The structure-activity relationships of azetidine-based DPP
IV inhibitors will be discussed in detail in the following
review. The azetidine-based DPP IV inhibitors can be divided
into three main subtypes, the 2-cyanoazetidines, 3-fluoroazetidines
and 2-ketoazetidines. These subtypes have been explored and
structure-activity relationships have been established by
several groups. Several compounds within each of these subtypes
display sub micromolar potency against DPP IV. The most potent
cyanoazetidines and ketoazetidines have large, hydrophobic
amino acid groups bound to the azetidine nitrogen and display
activities below 100nM. DPP IV inhibition is not sensitive
to stereochemistry at the 2-position as both 2-(R)- and 2-(S)-cyano
and –keto azetidines display similar inhibitory potencies.
While these “warhead”-based cyano- and ketoazetidines
have the potential for covalent, bond-forming inhibition,
they can also react to internally cyclize into inactive ketopiperazines
and dihydroketopyrazine. Thus, chemical instability was also
explored for compounds in these two subtypes and certain members
of the cyanoazetidine series display aqueous stability comparable
to the closely related cyanopyrrolidines. Select 3-fluoroazetidines
also display inhibitory potencies below 1μM
without the propensity for cyclization and chemical instability
associated with the other subseries.
[Back to top]
Molecular Recognition of Ligands in Dipeptidyl Peptidase
IV
Bernd Kuhn, Michael Hennig, and Patrizio Mattei
The serine protease dipeptidyl peptidase IV (DPP-IV) is a
clinically validated target for the treatment of type II diabetes
and has received considerable interest from the pharmaceutical
industry over the last years. Concomitant with a large variety
of published small molecule DPP-IV inhibitors almost twenty
co-crystal structures have been released to the public as
of May 2006. In this review, we discuss the structural characteristics
of the DPP-IV binding site and use the available X-ray information
together with published structure-activity relationship data
to identify the molecular interactions that are most important
for tight enzyme-inhibitor binding. Optimized interactions
with the two key recognition motifs, i.e. the lipophilic
S1 pocket and the negatively charged Glu 205/206 pair, result
in large gains in binding free energy, which can be further
improved by additional favorable contacts to side chains that
flank the active site. First examples show that the lessons
learned from the X-ray structures can be successfully incorporated
into the design of novel DPP-IV inhibitors.
[Back to top]
Prolyl Peptidases Related to Dipeptidyl Peptidase
IV: Potential of Specific Inhibitors in Drug Discovery
Pieter Van der Veken, Achiel Haemers and Koen Augustyns
Dipeptidyl peptidase IV (DPP IV) is a validated target
for the treatment of type 2 diabetes, with several inhibitors
currently in phase 3 clinical trials. This review will mainly
focus on proline-specific dipeptidyl peptidases related to
DPP IV: fibroblast activation protein (FAP), dipeptidyl peptidase
8 (DPP8), dipeptidyl peptidase 9 (DPP9) and dipeptidyl peptidase
II (DPP II). The biochemical and biological properties of
these enzymes will be discussed, as well as the therapeutic
potential of their inhibition. The development of potent and
selective inhibitors for each of these peptidases will be
described.
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