|
Items in cart [0] |
Questions? Call 888-624-8373 |
| Copyright © 2009. National Academy of Sciences. All rights reserved. Terms of Use and Privacy Statement |
Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter.
Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page 13
New Methods in Synthesis and
Development for Pharmaceuticals
Annual sales in the pharmaceutical industry have been growing in the double-
digit range for many years. These numbers are expected to decrease in the future
because of patent expirations on major products, pressure to reduce healthcare
expenditures, larger spending on sales and marketing, and the increased cost of
research and development. Because the market for the leading therapeutic classes
of drugs is over $350 billion per year, there is considerable incentive to pursue
opportunities for new drug discovery. These opportunities must be addressed,
however, in the face of fierce competition in an industry that is consolidating and
experiencing considerable pressure on pricing. These factors will require intelli-
gent and efficient management of the significant risks and costs associated with
pharmaceutical research and development.
Finding safe, effective medicines has always been the goal of the pharma-
ceutical industry. Better understanding of the biochemical mechanisms for dis-
eases has improved the scientific basis for drug discovery. It is anticipated that
genomics, proteomics, and bioinformatics will further enhance the drug discov-
ery process by providing a more advanced understanding of disease processes
and revealing new opportunities for successful intervention with drugs (see
Sidebar 2.1 J. These new tools, along with others such as high-throughput screen-
ing, combinatorial chemistry, and micro array technology have required signif~-
cant capital and human resource investments before the capture of clear value in
productivity. Subsequently, costs and risk in drug discovery increase before it can
be established that the new tools and technologies improve the efficiency of the
process. This is a challenge for the industry because cost effectiveness and
affordability of product are vital issues in drug discovery and development.
The pharmaceutical industry of today evolved largely from the chemical in-
13
OCR for page 14
14
:
HEALTH AND MEDICINE
Sidebar 2.1
The Trend toward Personalized Medicine
Excerpt from "Bioprocessing"
James R. Swartz ~
Stanford University
: :
The genomics revolution is working toward personalized medicine,
requiring precise diagnostics and rapid, Inexpensive drug production. In-
stead of providing one drug to serve a population, The possibility exists to
provide multiple drugs to serve that population by being more specific to
each individual patient. No product is on the~market~to capitalize on per
s~onalized medicine for any~illness, and: no technology exists that can
provide rapid production, low cost, and high Quality therapeutics. B-cell
Iymphoma provides art example, each patient has a different B-cell re-
ceptor, so each patient needs a different vaccine. The hypothesis is that
if the variable region of the B-cell receptor can be expressed and fused to
an immune-stmulating molecule and given to the ~patient, antibodies will
be stimulated and attack the disease. Geli-free synthesis is being exam-
~ined to potentially isolate the diseased cells to a DNA template In a few
days, produce the protein in a few hours, then punfy, formulate, test, and
release the remedy in about one week. The result would be personalized
:
~ medicine with the~required reduction in tideland expense.
dustry. As these roots would suggest, chemistry was a key component of early
drug discoveries that were focused on pain management and the treatment of
inflammation and infectious diseases. Advances in science related to the structure
and function of DNA, as well as powerful methods for manipulating DNA and
making proteins, has led to a more balanced partnership for drug discovery be-
tween chemistry and biology. Understanding the structure and function of these
biopolymers has provided a common language for the partnership to use for stra-
tegic and tactical purposes. The result was a commonly used process for drug
discovery. This process focused initially on four key points: (1) selection of a
therapeutic target, (2) linkage of the chosen target to a defined biological mecha-
nism of drug action, (3) discovery of a lead compound that worked by this mecha-
nism, and (4) optimization of the lead for potency and selectivity of the biological
activity. Pursuit of this scheme revealed the importance of including other con-
siderations in the optimization process at an early time point. Thus, drug absorp-
tion, distribution, and metabolism (ADMET) and certain safety studies were in-
corporated into the selection process for potential drug development candidates.
Questions related to "what the drug does to the body" and "what the body does to
the drug" are addressed in this scheme. While these additional studies add time
and expense to the discovery phase of the process, justification for this comes
OCR for page 15
NEW METHODS IN SYNTHESIS AND DEVELOPMENT FOR PHARMACEUTICALS 15
from higher-quality compounds being entered into the more expensive develop-
ment phase of the overall process that leads to a new drug.
Selection of a therapeutic target based on unmet or undermet clinical need is
an important early step in drug discovery. Increased use of outcome studies to
establish the therapeutic value of new medicines has raised target choice to a new
level of sophistication. Third-party players may require a study of this type for
reimbursement. Because outcome studies can be difficult to design and expensive
to execute, it is important to carefully research this issue as part of the initial
project proposal.
BIOLOGICAL PATHWAYS
The explosion of information regarding biological pathways, such as gene
and protein expression, modulation and regulation, and cell signaling, raises the
challenge of target selection to critical importance, given the immense effort re-
quired to discover and develop compounds. Once the therapeutic target has been
selected, linking the target with a specific biological mechanism for drug action
provides focus for the discovery. To accomplish this goal it is necessary to iden-
tify the relevant biological assays. An example is provided by the work that led to
the discovery and development of HIV protease inhibitors for treatment of HIV
infection. This viral enzyme is required for replication. A cell-free assay in which
enzyme inhibition could be measured was used to define the biological mecha-
nism of drug action. Compounds that were active in the enzyme assay were then
evaluated in cell culture systems that were subjected to lIIV infection. Com-
pounds that act by this mechanism and can achieve an adequate concentration in
these cells would be expected to inhibit viral replication in a concentration-de-
pendent manner. Thus, data from these two assays provided a useful coupling
between the mechanism of drug action and the expected response. Medicinal
chemists used data from these assays to guide progress from early lead com-
pounds to clinically effective drugs.
SCREENING
Leads for drug discovery are frequently identified by screening collections
of compounds available from synthesis or by isolation from natural sources. In
that these collections or libraries of compounds may be large (> 100,000), high-
throughput screening methods and equipment have been developed to facilitate
the work. In certain cases it has been possible to generate a lead by modifying the
structure of a substrate involved in the biological mechanism that is being stud-
ied. Medicinal chemists who use synthetic organic chemistry and a variety of
design tools and techniques pursue optimization of lead molecules for therapeutic
properties. The two central issues faced by the medicinal chemist are "what to
make" and "how to make it." The how-to-make knowledge is derived largely
OCR for page 16
16
HEALTH AND MEDICINE
from synthetic organic chemistry. Because many drugs have at least one stereo
center, recent major advances in synthetic methods addressing this issue have
been of particular importance to medicinal chemistry. Parallel methods for rap-
idly making analogs of leads have been useful in some cases. Multiple factors are
involved in deciding what to make. In as much as most drug molecules interact
noncovalently with their macromolecular targets, steric, electronic and salvation
factors make important contributions to the interaction energy. Design of biologi-
cally active molecules is not an exact science. Nonetheless, structure activity
relationships derived from laboratory experiments and modeling data frequently
contribute to the decisions about which drug to pursue. More recently, informa-
tion obtained from NMR and X-ray structures of target macromolecules with and
without complexed ligands has aided the design process.
While design of drug-like molecules for target affinity and selectivity is im-
portant, these molecules must also be optimized for pharmacokinetic, metabolic,
physical, and toxicological properties. As a result, p450 metabolic profiling, cas-
sette dosing in animals, cellular toxicity measurements, and the assessment of
protein binding and solubility properties have become routine in the ranking of
candidate compounds. The inclusion of these studies in the early phase of drug
discovery has improved the quality of compounds selected for further develop-
ment work. Because of their value, these data have rapidly become a significant
part of the information base used by medicinal chemists to recommend com-
pounds for development.
MECHANISM OF DRUG ACTION
Focusing on the mechanism of drug action has facilitated the discovery pro-
cess. Angiotensin converting enzyme (ACE) inhibitors and angiotensin-II recep-
tor antagonists have greatly improved therapy for the treatment of hypertension.
Better control of cholesterol biosynthesis through the use of HMG-CoA reduc-
tase inhibitors has reduced the incidence of coronary heart disease by more than
one-third. Bone resorption inhibitors have provided effective therapy for the treat-
ment of osteoporosis. Leukotriene receptor antagonists have improved the quality
of life for patients with asthma. Serotonin agonists with receptor subtype speci-
ficity have provided effective treatment for migraine headache. Improved therapy
for depression and schizophrenia also has been derived from agents that have
receptor subtype profiles that differ from earlier drugs of these types. The discov-
ery of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors
has dramatically improved prospects for patients infected with HIV. While the
therapeutic advances of the last quarter-century are impressive, many opportuni-
ties and challenges remain. Better drugs are needed to treat cancer, dementia,
obesity, diabetes, and infectious diseases. As this short and certainly not all-in-
clusive list would suggest, there is no shortage of opportunities for new drug
discovery.
OCR for page 17
HEW METHODS IN SYNTHESIS AND DEVELOPMENT FOR PHARMACEUTICALS 17
Organizational structures and relationships that will facilitate teamwork and
open sharing of information must be developed and used in order to achieve
success in the complex world of drug discovery. The workforce must be able to
function as an interdisciplinary team, consisting of chemists, biologists, and sci-
entists who specialize in molecular modeling, computational analysis, structure
determination, drug metabolism, pharmaceutics, safety assessment, and all as-
pects of informatics. Because there are many tools that the team uses, such as
high-throughput screening, combinatorial chemistry, genomics, and proteomics,
produce large amounts of data, the team must have access to the resources needed
to process this information. Open access to all information is important to encour-
age boundary crossing in the search for innovative solutions in each drug discov-
ery project.
Structural analysis of target macromolecules using protein X-ray crystallog-
raphy and NMR spectroscopy has already had a positive impact on drug design.
Powerful computational programs and modeling techniques have enhanced the
utility of these methods. It is likely that this trend will continue as new science
evolves. Mass spectrometry, particularly in the fields of bioavailability and me-
tabolism, has been key to rapidly obtaining information that is very useful in the
candidate optimization process. While the promise of proteomics, genomics, and
bioinformatics is yet to be realized, the potential of this new science to signifi-
cantly facilitate drug discovery is real. The continuing advances of synthetic or-
ganic and analytical chemistry are also important to the pharmaceutical industry.
Advances in parallel synthesis have the potential to rapidly expand the diversity
of compounds available for study as new drugs. New chemistry that makes pro-
duction of drugs more efficient has obvious commercial value. Continuing in-
vestment in all of the science that supports the advancement of knowledge at the
interface between chemistry and biology is critical to achieving the full value of
what we have already learned.
TISSUE ENGINEERING
Research in tissue engineering has focused on developing nonimmunogenic
materials to serve as scaffolds for regeneration of damaged tissue. This technol-
ogy is now being applied to generate skin for severe burn victims to decrease the
time required for healing and in cases where the damaged area is too large to
cover with normal grafts of skin from another part of the patient's body. One
relatively low-cost approach uses an "artificial skin" to cover the burned area.
The need for skin grafts and scarring is greatly reduced. Another approach uses
"living skin," a synthetic matrix with cells in the matrix, but the current cost of
this material renders it impractical and cannot yet compete with approaches that
do not involve the external use of cells. There are many potential applications of
the technology that will require the development of new polymer matrixes with
OCR for page 18
18
HEALTH AND MEDICINE
superior properties that will be absorbed or encourage adhesion of the appropriate
cells and permit the development of blood vessels for oxygen transport.
Research is underway to develop materials for synthetic bone grafts. Patients
with osteosarcoma often require removal of large sections of bone. Currently the
only option for replacement is cadaver bone. These grafts carry the potential of
disease transmission, require an available source of replacement bone, heal
slowly, and are weaker than the bone that was replaced. A totally synthetic scaf-
fold for growth of new bone will need to interact with cells in the body in a
manner that attracts those cells required for healing to the wound site (e.g., the
cells for depositing bone and those for forming the blood vessels needed to carry
oxygen to the new tissue). This might be accomplished by designing new materi-
als that interact with adhesion receptors on cells and the development of drugs
that promote cell migration and proliferation. The set of molecular tools available
is limited at this point, and additional work is needed to identify and characterize
new receptors and molecules that stimulate cell migration and growth. The ligands
that interact directly with cell surface adhesion receptors must be clustered to
achieve their maximum effect. New synthetic procedures are needed to produce
biocompatible polymers for which the concentration and presentation of ligands
for adhesion of specific types of cells can be precisely controlled.
Polymer scaffolds can be used to grow bone and cartilage at the present time.
One of the visions in the field of tissue engineering, which is well beyond the
capabilities of current technology, is to be able to grow organs such as a kidney,
heart, or liver on polymer templates. Fully developed organs are large complex
structures with a complex vascular network to deliver oxygen and nutrients. Early
experiments have highlighted problems associated with supplying oxygen to cells
as newly growing tissue becomes more than a few microns thick.
A more tractable application of the technology for growing heart, liver, kid-
ney, or lung tissue may lie in the development of "tissue chips" for drug develop-
ment. For example, hepatitis C is the leading cause of liver transplants in the
Western world. Attempts to develop new drugs for hepatitis C have been frustrat-
ing because the virus infects only humans and chimpanzees and efforts to propa-
gate the virus outside animals have been unsuccessful. In a related vein, liver
toxicity from drugs such as acetaminophen or consumption of poisonous mush-
rooms can result in death. The mechanisms that lead to necrosis and death are just
now being elucidated in mice. Related studies cannot be done in humans, and an
understanding of these diseases is being hampered by the lack of good models for
how humans, not mice, respond to infection, or to the chronic or acute insults that
result in liver damage. Similar problems are encountered with other organs.
The development of tissue chips comprising polymer-supported human cells
that retain the functions normally associated with intact organs such as the liver
would allow drug development to proceed with human tissue rather than resort-
ing to animal models. Several advantages of such a development are immediately
OCR for page 19
NEW METHODS IN SYNTHESIS AND DEVELOPMENT FOR PHARMACEUTICALS 19
apparent. For example, research related to drug development and toxicity assess-
ments would not require the heavy reliance on the current practice of test animals.
Ultimately, costs for drug development could be lowered, the effects of drugs on
specific human tissues could be readily assessed, and ethical concerns about the
use of animals in drug screening would be eliminated. In any event, the techno-
logical problems to be solved are immense. A liver cell only remains a liver cell
when it is in constant contact with its neighboring hepatic cells. Without the
constant signals that cells get from their neighbors, they loose their sense of place
and the related behavior they exhibit in intact tissue. One possible approach is to
perfuse matrix-supported cells with the appropriate signaling molecules. How
closely their properties mimic those of cells in an organ could be assessed by
transcriptional profiling. The first step would involve chips consisting of a single
cell type, but normal tissue often contains several different cell types and ulti-
mately one would want to construct complex matrixes containing all the cells
found in the tissue in a proper spatial arrangement.
Several hurdles must be overcome to develop this technology. A new gen-
eration of three-dimensional materials must be synthesized that permit different
cell types to bind to specific regions of the support with high spatial selectivity.
Small molecules that support the signaling between cells typically found in or-
gans must be identified and synthesized. Manufacturing techniques must be de-
veloped to make the technology cost effective. The scientists and engineers who
develop this technology must have a firm base in chemistry and chemical engi-
neering and be broadly trained so they understand the special challenges posed by
working with tissue. Most undergraduate and many graduate programs are not
designed for the breadth of exposure needed to tie together such different fields
while retaining the in-depth training in a subdiscipline. Thus, the curricula of-
fered by colleges and universities will also need attention.
ACCESS TO INFORMATION
More than ever innovation requires the sharing of information across novel
technologies, chemistry efforts, and biological fields - information that becomes
fragmented when spread across academic labs and small biotech companies. Deal-
ing with fragmentation of scientific knowledge is critical for future successes in
the fields of health and medicine. In addition to keeping abreast of new insights,
access has become a challenge. One solution has been to place information in the
public domain (although protecting intellectual property often delays disclosure
or constrains use); another has been to establish cross-company and -university
alliances. The need for biotech alliances with large pharmaceutical companies is
acknowledged by small private companies, both for the shared learning and fi-
nancial support that large partners can provide. From the large pharmaceutical
perspective, "enabling technologies" have been fair game for licensing-in for
OCR for page 20
20
HEALTH AND MEDICINE
many years. A more recent revelation is that alliances of small biotech companies
and universities are equally important to bring chemical and biological innova-
tion into large pharmaceutical companies. In a similar vein, collaborations across
small biotech companies and universities may become much more the norm for
cross-discipline integration. Current alliance structures are not efficient; new ap-
proaches are needed.
Representative terms from entire chapter:
drug action
