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Current Topics
in Medicinal Chemistry
ISSN: 1568-0266
Current Topics
in Medicinal Chemistry
Volume 5, Number 10, 2005
Contents
p38 Kinase Inhibitor
Guest Editor: Katerina Leftheris
Editorial Pp.919
The Biology of p38 Kinase: A Central Role in Inflammation
Pp.921
Gary L. Schieven
[Abstract]
Potential Adverse Effects Associated with Inhibition
of p38α/β
MAP Kinases Pp.929
Donna M. Dambach
[Abstract]
Discovery of Highly Selective Inhibitors of p38α
Pp.941
Ioana Popa-Burke, Steve Birkos, Leonard Blackwell, Lynn
Cheatham,Jennifer Clark, John K. Dickson, Jr., Scott Galasinski,
William P. Janzen,Jose Mendoza, Jennifer L. Miller, Robert
P. Mohney, Paul M. Steed and C. Nicholas Hodge
[Abstract]
The Discovery of Novel Chemotypes of p38 Kinase Inhibitors
Pp.953
David J. Diller, Tsung H. Lin and Axel Metzger
[Abstract]
Small Molecule p38 Inhibitors: Novel Structural Features
and Advances from 2002–2005 Pp.967
John Hynes, Jr. and Katerina Leftheris
[Abstract]
P38 MAP Kinase Inhibitors: Evolution of Imidazole-Based
and Pyrido-Pyrimidin-2-One Lead Classes Pp.987
Swaminathan R. Natarajan and James B. Doherty
[Abstract]
Structural Comparison of p38 Inhibitor-Protein Complexes:
A Review of Recent p38 Inhibitors Having Unique Binding Interactions
Pp.1005
Stephen T. Wrobleski and Arthur M. Doweyko
[Abstract]
Pathway to the Clinic: Inhibition of P38 MAP Kinase
A Review of Ten Chemotypes Selected for Development Pp.1017
David M. Goldstein and Tobias Gabriel
[Abstract]
Abstracts
[Back to top]
Editorial
P38 Kinase Inhibitor:
The last several years have seen an explosion of interest
in developing inhibitors to kinases found critical to the
pathogenesis of disease. Improvements in screening techniques,
surveying kinase selectivity and understanding the side-effects
of kinase inhibition have made targeting kinases for therapeutic
intervention more attainable.
Development of p38≹ MAP kinase inhibitors for the treatment
of inflammatory disease has historically been elusive for
several reasons. Different structural classes appeared to
have different toxicity profiles both in animal studies and
in the clinic. Furthermore, several of the compounds with
reported data were determined not to be highly selective for
p38≹ further compounding the issue of whether the toxicities
observed were p38≹ related. Recent advances in our understanding
of p38-related mechanisms as well as significant improvements
in the ability to screen compounds for kinase selectivity
suggest there may be opportunities to overcome these issues.
To fully explore recent advances in the p38 field, Current
Topics in Medicinal Chemistry has devoted this entire issue
to a review of the current chemistry and biology of p38 inhibition.
The initial article authored by Gary Schieven from Bristol-Myers
Squibb provides a biological background for why p38? kinase
activation leads to inflammation at the cellular level and
the mechanisms by which p38? regulates gene expression. Donna
Dambach from Bristol-Myers Squibb describes potential adverse
effects of p38 inhibition as well as what is known though
KO mouse technology and published disclosures from clinical
trials. Ioana Papa-Burke and her colleagues from Amphora describe
the use of microfluidic technology to rapidly screen compounds
against a collection of more than 60 kinases enabling a very
rapid and accurate identification of multiple scaffolds. David
Diller and his colleagues from Pharmacopeia further describe
advances in selectivity screening for kinases. John Hynes
and K. Leftheris from Bristol-Myers Squibb provide a survey
of the p38 kinase inhibitor patent and published literature
over the last several years and describe new chemotypes that
have been disclosed. Ravi Natarajan and James Doherty from
Merck describe the development of novel quinazolinone and
associated chemotypes as p38 inhibitors. Steve Wrobleski and
Arthur Doweyko from Bristol-Myers Squibb co-authored a review
of known X-ray structures of p38 inhibitor-enzyme complexes.
They describe the current understanding of structural elements
and interactions that may play a role in how p38 inhibitors
bind to the enzyme. Finally, David Goldstein and Tobias Gabriel
from Roche review ten chemotypes that were selected for development
and describe data obtained from clinical trials.
With a number of companies in clinical trials with p38 inhibitors,
it should become clear in the near future whether this attractive
target for suppressing inflammation can lead to a marketed
drug for p38-mediated diseases.
I would like to express my gratitude the following individuals
who served as manuscript reviewers for this issue:
J. Das, M. Dhar, A. Dyckman and S. Wrobleski.
Finally, I am grateful to all the authors for their timely
and well written contributions in what we hope will be an
informative contribution to the field.
Katerina Leftheris
Pharmaceutical Research Institute
Bristol-Myers Squibb
Princeton, NJ 08543-4000,
USA
E-mail: katerina.leftheris@bms.com
[Back to top]
The Biology of p38 Kinase: A Central Role in Inflammation
Gary L. Schieven
The p38 kinase plays a central role in inflammation, and
it has been the subject of extensive efforts in both basic
research and drug discovery. This review summarizes the biology
of the p38 kinase with a focus on its role in inflammation.
The p38 kinase regulates the production of key inflammatory
mediators, including TNFα,
IL-1β,
and COX-2. In addition, p38 also acts downstream of cytokines
such as TNFα,
mediating some of their effects. The potential efficacy of
p38 inhibitors may thus be greater than would be expected
from the inhibition of the mediators alone. Inhibitors of
p38 kinase are currently in development for the treatment
of rheumatoid arthritis. The biological processes regulated
by p38 kinase suggest a wide variety of additional potential
indications.
[Back to top]
Potential Adverse Effects Associated with Inhibition
of p38α/β
MAP Kinases
Donna M. Dambach
Inhibitors of p38 MAP kinases show promise for the treatment
of inflammatory and immunological disorders and some cancers.
There is a substantial body of experimental evidence across
several organ systems suggesting that p38 also mediates developmental,
differentiation and proliferation processes. As a consequence
of the wide-ranging regulatory role of p38 kinase in diverse
cellular processes, the possibility of adverse events resulting
from undesired pharmacological activity is a major concern
for the p38 inhibitor drug class. Taking into consideration
the limitations of experimental modeling systems, together
the data may indicate that profound inhibition of p38 has
the potential to impact these processes during fetal or neonatal
development. The difficulty comes in extrapolating these findings
to predict potential adverse effects under conditions of partial
inhibition of p38 activity, and in an adult population in
which these processes are typically only recapitulated during
repair or adaptive responses. As such, the goal of this review
of the targets of p38 activity is to bring an awareness of
the those organ systems that should be monitored for potential
toxicity, as well as to present a potential mechanistic basis
for such monitoring or for investigation of adverse effects
that may develop with administration of a p38 inhibitor.
[Back to top]
Discovery of Highly Selective Inhibitors of p38α
Ioana Popa-Burke, Steve Birkos, Leonard Blackwell,
Lynn Cheatham,Jennifer Clark, John K. Dickson, Jr., Scott
Galasinski, William P. Janzen,Jose Mendoza, Jennifer L. Miller,
Robert P. Mohney, Paul M. Steed and C. Nicholas Hodge
The p38 MAP kinases are a family of serine/threonine protein
kinases that play a key role in cellular pathways leading
to pro-inflammatory responses. We have developed and implemented
a method for rapidly identifying and optimizing potent and
selective p38α
inhibitors, which is amenable to other targets and target
classes. A diverse library of druggable, purified and quantitated
molecules was assembled and standardized enzymatic assays
were performed in a microfluidic format that provided very
accurate and precise inhibition data allowing for development
of SAR directly from the primary HTS. All compounds were screened
against a collection of more than 60 enzymes (kinases, proteases
and phosphatases), allowing for removal of promiscuous and
non-selective inhibitors very early in the discovery process.
Follow-up enzymological studies included measurement of concentration
of compound in buffer, yielding accurate determination of
Ki and IC50 values, as well as mechanism
of action. In addition, active compounds were screened against
less desirable properties such as inhibition of the enzyme
activity by aggregation, irreversible binding, and time-dependence.
Screening of an 88,634-compound library through the above-described
process led to the rapid identification of multiple scaffolds
(>5 active compounds per scaffold) of potential drug leads
for p38? that are highly selective against all other enzymes
tested, including the three other p38 isoforms. Potency and
selectivity data allowed prioritization of the identified
scaffolds for optimization. Herein we present results around
our 3-thio-1,2,4-triazole lead series of p38α
selective inhibitors, including identification, SAR, synthesis,
selectivity profile, enzymatic and cellular data in their
progression towards drug candidates.
[Back to top]
The Discovery of Novel Chemotypes of p38 Kinase Inhibitors
David J. Diller, Tsung H. Lin and Axel Metzger
In the late 1970s and the early 1980s the initial p38 chemotype,
the triaryl imidazoles, was discovered as an off-target effect
during the development of cyclooxygenase and 5-lipoxygenase
inhibitors long before the identity of the p38 kinase was
known. During the last 10 years a number of novel p38 chemotypes
were discovered via high throughput screening. More recently,
the first series of p38 inhibitors discovered by xray crystallographic
and virtual screening was announced. Finally, throughout the
life span of p38 drug discovery programs significant medicinal
chemistry effort has continually been placed on the design
of new inhibitors from known chemotypes using molecular modeling,
protein crystallography, hybrid design and simply sound intuition.
Indeed, the search for p38 kinase inhibitors offers an excellent
historical perspective as to how technological changes that
have taken place in the pharmaceutical industry over the last
decade, have affected the ways in which new leads are discovered
and advanced. It is the intent of this review to highlight
the discoveries of novel p38 chemotypes, emphasizing where
possible the key technologies used in the discoveries and
the knowledge gained from each discovery.
[Back to top]
Small Molecule p38 Inhibitors: Novel Structural Features
and Advances from 2002–2005
John Hynes, Jr. and Katerina Leftheris
The discovery and development of selective, efficacious,
and safe small molecule p38 mitogen-activated protein kinase
inhibitors for the treatment of inflammatory diseases remains
the focus of many pharmaceutical research programs. Advances
in small molecule p38 inhibitor design in potency and oral
efficacy have been accelerated with the large number of available
inhibitor-enzyme x-ray structures. These advances have allowed
for the discovery of diverse sets of inhibitors with the opportunity
to map inhibitor interactions and design selective inhibitors.
This review covers recent compound disclosures in the patent
and published literature over the last three years. Many disclosures
represent new chemotypes as well as creative modifications
of known structures.
[Back to top]
P38 MAP Kinase Inhibitors: Evolution of Imidazole-Based
and Pyrido-Pyrimidin-2-One Lead Classes
Swaminathan R. Natarajan and James B. Doherty
The initial disclosure of tri-substituted imidazole-based
drug molecules such as 1 for inhibition of p38 MAP kinase
by SmithKline Beecham (SB) sparked an effort in this area
at Merck and other pharmaceutical research establishments.
Although analogs in this class have shown good inhibitory
properties against p38 MAP kinase, their selectivity profile
were modest and left much room for improvement. Attempts to
discover newer compounds with improved selectivity over the
prototypical SB compound 203580 (1), led to the discovery
of a new sub-class of p38 inhibitors typified by compound
18 at Merck. Although this benchmark compound was potent,
highly selective and orally efficacious it was burdened with
compound related adverse effects in dogs that has delayed
further development. In 1999, a new class of p38 inhibitors
represented by clinical candidate VX-745 (26), was disclosed
by Vertex Pharmaceuticals. This compound displayed unprecedented
selectivity due to its unique mode of binding to the active
site in p38 MAP kinase. Inspired by the exquisite selectivity
profile of VX-745 [26] a scaffold re-design was initiated
at Merck which resulted in the discovery of the quinazolinone,
pyrimido-pyrimidone, pyrido-pyrimidone, quinolinone and naphthyridinone
based p38 inhibitors.
[Back to top]
Structural Comparison of p38 Inhibitor-Protein Complexes:A
Review of Recent p38 Inhibitors Having Unique Binding Interactions
Stephen T. Wrobleski and Arthur M. Doweyko
Small molecule inhibition of protein kinases in the treatment
of significant diseases such as cancer, Alzheimer’s
disease, diabetes, and rheumatoid arthritis has attracted
significant attention over the past two decades and has clearly
become one of the most significant challenges for drug discovery
in the 21st century. While the recent identification of 518
different kinases in the human genome has offered a wealth
of opportunities for drug intervention in the treatment of
these diseases, it has also created a daunting challenge with
respect to selective kinase inhibition as a viable strategy
in target-based drug design. Over the past decade, the design
and development of a small molecule that selectively inhibits
the p38 mitogen activated protein (MAP) kinase has clearly
emerged as one of these challenges within the industry. This
review will focus on the comparison of the x-ray crystal structures
and binding models of the most recent p38 inhibitor-enzyme
complexes and the identification of the structural elements
and interactions that may be important in providing inhibitor
potency and selectivity toward the p38 MAP kinase.
[Back to top]
Pathway to the Clinic: Inhibition of P38 MAP Kinase
A Review of Ten Chemotypes Selected for Development
David M. Goldstein and Tobias Gabriel
p38 mitogen activated protein (MAP) kinase remains the most
compelling therapeutic target for oral drug intervention for
a wide range of autoimmune disorders based on the central
role this enzyme plays in inflammatory cell signaling. Efforts
to discover inhibitors of p38 suitable for clinical investigation
have continued to escalate in part due to the incredible diversity
of unique chemotypes reported to inhibit the enzyme. Since
1993, at least seventeen p38 inhibitors have been reported
to have entered into clinical trials. Next generation inhibitors
have been disclosed with improved potency for p38 and enhanced
selectivity versus other protein kinases. Over the last three
years, there have been multiple reports of cytokine suppression
in humans following oral administration of p38 inhibitors.
These results, in addition to proof of concept studies in
rheumatoid patients, have established p38 inhibition as an
avenue for the future management of pro-inflammatory cytokine
based diseases. This review describes the discovery at Roche
of novel p38 inhibitors which have advanced into clinical
trials. The pharmacology of the Roche compounds is then compared
with eight chemically distinct p38 inhibitors known to have
entered clinical development.
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