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Chemistry International
Vol. 24, No. 5
September 2002
Medicinal
Chemistry in the New Millennium
The entry into a new
millennium has been accompanied by unrelenting growth in the rate of scientific
discovery, and this is no better exemplified than in the field of medicinal
chemistry. This subject has flourished under the influence of major advances
in the component disciplines that make it distinctive, but continues to
be confronted by new opportunities to explore and refine the predictive
potential of drug design in response to the quest for greater selectivity
and subtlety to meet new challenges to human health. A special topic article
in Pure and Applied Chemistryappears in this context very timely. The
author, Paul W. Erhardt, has undertaken the mammoth task of addressing
this complex and rapidly evolving field of endeavor, and offers his distinctive
interpretation and vision of challenges and opportunities. The following
has been extracted from the article abstract and introduction that appeared
in Pure and Applied
Chemistry, Vol. 74, No. 5, pp. 703-785 (2002).
A Glance
Into the Future
by
Paul W. Erhardt
The future
of medicinal chemistry as both a pure and an applied science has been
considered relative to trends that are already having a significant
impact upon drug discovery and development. Such trends include pursuing
therapeutic efficacy, addressing 3-D structure within database settings,
assuring absorption, directing distribution, controlling metabolism,
optimizing elimination, and avoiding toxicity. As the exploration of
these topics proceeds by deploying combinatorial chemistry coupled to
high-throughput screening, medicinal chemistry will play a key role
in interpreting the underlying structureactivity relationships. This
will cause the overall process of drug discovery and development to
be knowledge generating. As fundamental knowledge accumulates across
all of these areas, virtual approaches will eventually become firmly
anchored to experimental and theoretical databases having validated
clinical predictability.
Given
the highly interdisciplinary nature of medicinal chemistry and its potential
applications across a myriad of future life-science research activities,
the review presented in Pure and Applied Chemistry is necessarily limited
only to those possibilities that stand out upon taking a broad purview
of the fields most prominent trends. From this vantage point,
however, at least a glance is cast toward some of the more exciting
opportunities for the future of medicinal chemistry. The document includes
nine sections. Each sections overview presented below lists what
topics are and are not covered and indicates the reasoning behind these
choices. It also describes the consistent tone that was sought while
attempting to elucidate the numerous technologies that necessarily become
encompassed by the variously highlighted activities.
As
fundamental knowledge accumulates across all of these areas, virtual
approaches will eventually become firmly anchored to experimental
and theoretical databases having validated clinical predictability.
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While
initially contemplating how medicinal chemistry might continue to evolve
as both a basic and applied science, it became apparent that it would
be useful to first consider where medicinal chemistry has been and how
it has come to be what it is today. Thus, toward quickly establishing
a context from which the future might be better appreciated, and perhaps
even seen to already be repeating itself amongst a new set of players
and technologies. Section 2Practice of Medicinal Chemistry
provides a short discourse about medicinal chemistrys emergence
as a formalized discipline, its early developments, and its present
status by considering how medicinal chemistry has been practiced across
jumps
of about 25-year increments. This section does not include a chronological
list of medicinal chemistrys many contributions, nor does it highlight
the many accomplishments of its noted investigators. Both of the latter
can be found elsewhere as part of more traditional, historical treatments.
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Non-linear Relationship
of Medicinal Chemistry to Basic and Applied Research. Adapted
from a figure provided by F.A. Cotton (Chem. Eng. News
Dec. 4, p. 5, 2000) as part of his summary and commentary about
a book entitled "Pasteurs Quadrant" (D.E. Stokes,
Brooking Press, Washington, DC, 1997). |
Medicinal
chemistrys near and longer-term futures are considered in Section
3Evolving Drug Discovery and Development
Process relative to several of todays trends that
are already having a major impact upon the drug discovery process. A
working definition for medicinal chemistry is recited at the opening
of this section so that medicinal chemistrys immediate and future
roles can be more clearly ascertained. Section 3 also sets the stage
to later consider where several drug development topics may be headed
in the near and longer term.
Discussions
about gene therapy, vaccines, and biotech-derived therapeutic agents
have not been included in Section 4Pursuing Efficacy,
which addresses medicinal chemistry s continued pursuit of efficacy.
The aforementioned topics primarily reside within the domains of other
disciplines. Readers are encouraged, however, to consult other reviews
offered for these areas in order to appreciate how their advances are
sure to have a dramatic impact upon future life-science research and
its interface with medicinal chemistry. Alternatively, because assessing
molecular conformation is such an integral part of practicing medicinal
chemistry, several aspects of this key topic are considered within Section
5Assessing and Handling Molecular Conformation.
In particular, the handling of chemical structures within database settings
(e.g., chemoinformatics) is discussed in detail.
Several
drug development topics are regarded as critical factors that will have
a pivotal influence upon medicinal chemistrys continuing evolution
in the future. Each of these topics is briefly addressed within Section
6ADMET Considerations. These key topics include
assuring absorption; directing distribution; controlling metabolism;
assisting elimination; and, avoiding toxicity (i.e., the traditional
absorption, distribution, metabolism, elimination, and toxicity [ADMET]
studies that previously have been undertaken by pharmaceutical companies
during the secondary stages of preclinical drug development). As an
important extension of the ADMET discussions, nutraceuticals considered
in parallel with pharmacological synergy are also addressed in this
section.
Issues
pertaining to medicinal chemistrys future roles in pharmaceutical
intellectual property (IP) and to trends associated with process chemistry,
are raised within Section 7Process Chemistry Considerations.
With todays highly publicized emphasis upon genomics and proteomics,
at least an abbreviated discourse about process chemistry is included
so that this fundamental aspect of medicinal chemistrys link with
synthetic chemistry remains appreciated. Thus, the unmet need for large-scale,
stereoselective synthetic methodologies is briefly discussed.
Click on image for larger view
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Practice of Medicinal Chemistry
(MC) in the New Millennium (reproduced from Section 3Evolving
Drug Discovery and Development Process)
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While
it is beyond the scope of this review to discuss the impact that progress
in each of several analytical methods is likely to have upon medicinal
chemistry, X-ray diffraction has been selected to provide a representative
discussion within Section 8Analytical Chemistry/X-ray
Diffraction. As is often acknowledged by researchers from
various disciplines, "science moves forward according to what it
can measure." Presently, there appear to be numerous promising
advances among various analytical techniques that can be used to study
drug-receptor interactions. For example, readers are encouraged to seek
other reviews in order to appreciate the potential impact that anticipated
developments in nuclear magnetic resonance (NMR inclusive of LCNMR and
high-flowthrough techniques), mass spectrometry (MS inclusive of LC-MS
and LC-MS/MS), microcalorimetry, and surface plasmon resonance may have
upon medicinal chemistry.
Section
9Summary serves as an overall summary for the
document. In addition it discusses some areas for concern, including
training of medicinal chemists, inventorship, and the interplay of patent
trends and future research within the context of IP.
The documents
running dialogue has been developed from future possibilities suggested
by the current medicinal chemistry and drug discovery literature, as
well as from general observations afforded while consulting with both
the private and public sectors. Descriptions of specific research projects
have been interspersed throughout so that real case examples, along
with their chemical structures, could be explicitly conveyed. A concerted
effort has been made to keep hype to a minimum. Alternatively, jargon
has been used whenever it was thought that such terms portray the mind-sets
that were important for a given period, or because a particular term
or phrase appears to be taking on an enduring significance. Some of
the more technical of these terms are listed in a table in Section 1
Introduction, along with a short definition in each case. Since several
acronyms have been used for repeating phrases, an alphabetical listing
of all acronyms and their definitions is provided to assist readers
as they move deeper into the document.
The potential
impact of some of the recent trends in process chemistry, and in analytical
chemistry using Xray diffraction as an exemplary method, are additionally
highlighted before reiterating the articles major points in Section
9. From this purview, the summary also considers the education of future
medicinal chemists, notes potential issues related to the future of
pharmaceutical-related IP, and concludes by alluding to a brewing paradox
between enhanced knowledge and enhanced molecular diversity relative
to the future discovery of new drugs.
Numerous
references to secondary scientific/primary news journals have been cited
because these journals are doing an excellent job of both reporting
the most recent trends and forecasting the potential future. In several
cases, a single citation has been used to list many of the informational
Web sites that can often be found for a given topic.
Topics
are considered into the future only for about 75 years, with the first
25 being regarded as near term, and the next 50 being regarded as long
term. The speculation that has necessarily been interjected throughout
the review was done with the thought that one of the goals for this
type of article is to prompt the broadest contemplation possible about
the future directions that medicinal chemistry might take. Finally,
the review considers medicinal chemistry as both a distinct, pure science
discipline and, equally important, as a key interdisciplinary, applied-science
collaborator seeking to mingle with what should certainly prove to be
an extremely dynamic and exciting environment within the life sciences
arena of the new millennium
<www.iupac.org/publications/pac/2002/7405/7405x0703.html>
About
the Author
Dr. Paul
W. Erhardt received a Ph.D. in medicinal chemistry from the University
of Minnesota in 1974 and undertook postdoctoral studies in the area
of bioanalytical chemistry and drug metabolism at the University of
Texas at Austin. His early career involved bench-level research as a
synthetic medicinal chemist within the pharmaceutical industry. He was
with American Critical Care in Chicago for about 10 years as a research
scientist, senior research scientist, and as a group leader. During
this period he was directly responsible for the chemical design, synthesis
and entire chemical-related pre-clinical/Phase I development of esmolol,
a drug presently marketed as Brevibloc.® He then joined Berlex Laboratories
in New Jersey as a Section Head where over the course of 10 years he
became the assistant director of medicinal chemistry in charge of drug
discovery and, finally, the assistant director across all pharmaceutical
research and development activities. When the research operation of
Berlex was merged with the biotechnology operations of two new corporate
purchases located on the West coast, he became the medicinal chemist
representative on a key task force that evaluated external technologies
for the purpose of maintaining the companys drug development pipeline.
During this period he became a Certified U.S. Patent Agent in order
to better deal with the patent issues that often accompany external
technology and its in-licensing. He also led the development of a unified
technology beschluss (decision making) document which harmonized
the optimal use of R&D resources across the Berlex/SAG corporate
triad (Europe, U.S., and Japan) relative to the progression of all internal
and in-licensed technologies from concept to market. With a lingering
desire to be closer to the day-to-day experimental practice of bench-level
medicinal chemistry, he returned to academia about seven years ago when
he joined the University of Toledo College of Pharmacy as a tenured
professor and director of the Center for Drug Design and Development.
During this latest period he was awarded the Colleges Outstanding
Faculty Award, and has stepped-in for one year as an acting assistant
dean so as to directly participate in the Colleges formal academic
accreditation process. Erhardt has also become active in IUPAC where
he has edited a book about using drug metabolism considerations during
drug design and development and where he has recently been voted president
elect for the IUPAC Division of Chemistry and Human Health. His present
research focuses on medicinal chemistry considerations pertaining to
oncology, soft drug technologies, ADMET-related SAR and synergy, and
chiral auxiliary synthetic reagents amenable to drug-related process
chemistry.
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