Download Structure-activity relationships

Medicinal Chemistry
Faculty member in charge: Professor (Penny Yu) 于沛
Other participating faculty
members:
王玉强, 陈卫民, 陈河如
Lecture time:
College:
Fall, 2009
Pharmacy (药学院药物化学教研室)
Textbooks
Requirements
1. Structure-activity relationships: In this course, we will provide the
student with an understanding and appreciation of the influence
chemical structures have on drug action (i.e., structure-activity
relationships);
2. Molecular features of drugs: To familiarize the student with molecular
features of drugs relating to (a) their stability in terms of shelf life and
(b) their compatibility in terms of physiochemical and therapeutic
characteristics;
3. Mechanisms of drug action: To render the student aware of mechanisms
of drug action at the molecular level and to provide insights as to how
physiochemical properties of drugs affect their activity and/or toxicity,
absorption, distribution, metabolism, and excretion;
4. Design and development of drug entities: To illustrate to the student
the significance of chemical structure, physiochemical properties,
and molecular modification in the rational design and development
of drug entities;
5. Drug nomenclature: To apprise the student of drug nomenclature,
including generic, proprietary, and chemical designations;
6. Therapeutic applications: To relate drug chemistry to the principal
therapeutic applications of medicinal agents.
Chapter 1
Introduction
1.
What is medicinal chemistry
2.
How to study medicinal chemistry
3.
How drugs are named
4.
History of medicinal chemistry development
Medicinal or pharmaceutical chemistry is a scientific discipline at
the intersection of chemistry and pharmacology involved with designing,
synthesizing and developing pharmaceutical drugs. Medicinal chemistry
involves the identification, synthesis and development of new chemical entities
suitable for therapeutic use. It also includes the study of existing drugs, their
biological properties, and their quantitative structure-activity relationships
(QSAR). Pharmaceutical chemistry is focused on quality aspects of medicines
and aims to assure fitness for the purpose of medicinal products.
Medicinal chemistry is a highly interdisciplinary science combining organic
chemistry with biochemistry, computational chemistry, pharmacology,
pharmacognosy, molecular biology, statistics, and physical chemistry.
Medicinal Chemistry involves:
• Synthesis
• Structure-Activity Relationships (SAR)
• Receptor interactions
• Absorption, distribution, metabolism, and excretion (ADME)
C1.1. Historial development of medicinal chemistry
Since the mid-19th century, pharmaceuticals have moved from the periphery to the
center of health care. In the course of that transition, a new industry sector
expanded to global scope, the field of medicinal chemistry rose to its current
prominence
The EARLY TIMES
Earliest medicines:
~ 5100 years ago
Chinese emperor Shen Nung - book of herbs, Pen Ts’ao
Ma Huang - contains ephedrine; used as a heart stimulant and for asthma. Now
used by body builders and endurance athletes because it quickly converts fat into
energy and increases strength of muscle fibers.
Ginseng:
Indications:
an anti-stress and mediator of well-being
History: thousands of years.
EMERGENCE OF PHARMACEUTICAL SCIENCE AND INDUSTRY:
1870-1930
The modern pharmaceutical industry traces its origin to two sources: apothecaries
that moved into wholesale production of drugs such as morphine, quinine, and
strychnine in the middle of the 19th century and dye and chemical companies that
established research labs and discovered medical applications for their products
starting in the 1880s. Merck, for example, began as a small apothecary shop in
Darmstadt, Germany, in 1668, only beginning wholesale production of drugs in
the 1840s.
A merging of these two types of firms into an identifiable pharmaceutical industry
took place in conjunction with the emergence of pharmaceutical chemistry and
pharmacology as scientific fields at the end of the 19th century.
Pharmaceutical firms, first in Germany in the 1880s and more recently in the U.S.
and England, established cooperative relationships with academic labs. Postulated
by Paul Ehrlich in 1906 following more than a decade of research, the concept
that synthetic chemicals could selectively kill or immobilize parasites, bacteria,
and other invasive disease-causing microbes would eventually drive a massive
industrial research program that continues to the present.
In 1897, a chemist at Bayer, Felix Hoffmann, first synthesized aspirin, another
staple of our medicine cabinets. The end of the 19th century also saw the
development of several important vaccines, including those for tetanus and
diphtheria.
Nevertheless, at the start of the 1930s, most medicines were sold without a
prescription and nearly half were compounded locally by pharmacists. While the
medical profession was well-established in Europe and America, the
pharmaceutical industry was only beginning to develop medicines to treat pain,
infectious diseases, heart conditions, and other ailments. Direct application of
chemical research to medicine appeared promising, but only a few substances-newly isolated vitamins and insulin--were more effective than treatments available
at the turn of the century.
THE PHARMACEUTICAL GOLDEN ERA: 1930 – 60
The middle third of the 20th century witnessed a blossoming of pharmaceutical
invention, with breakthroughs in the development of synthetic vitamins,
sulfonamides, antibiotics, hormones (thyroxine, oxytocin, corticosteroids, and
others), psychotropics, antihistamines, and new vaccines. Several of these
constituted entirely new classes of medicines. Deaths in infancy were cut in half,
while maternal deaths from infections arising during childbirth declined by more
than 90%. Illnesses such as tuberculosis, diphtheria, and pneumonia could be
treated and cured for the first time in human history.
SCALE-UP
Sir Alexander
Fleming (front)
in 1945 at a
pharmaceutical
production
facility.
SOCIAL REASSESSMENT, REGULATION, AND GROWTH: 1960-80
The pharmaceutical industry was buffeted by significant scientific, medical,
political, and market forces between 1960 and 1980. Approaches to drug
discovery and early-stage testing changed as medical advances made it
possible to identify compounds that block specific physiological processes.
Major innovations were made in cardiovascular drugs (starting with
antihypertensives and beta-blockers in the 1960s, followed by calcium-channel
blockers, ACE inhibitors, and cholesterol-reducing drugs in the 1970s and
1980s).
MARKET CHALLENGES, PATIENTS AND ACTIVISTS, AND
INDUSTRY CONSOLIDATION: 1980 – PRESENT
During the past two decades, the pharmaceutical industry has brought a new
wave of medicines to market that act on the central nervous system, offer
treatment for viral and retroviral infections (including therapies for HIV/AIDS),
and cure or delay the onslaught of cancer. At the same time, new biotech
medicines such as interleukins and interferon have been able to mimic or
support key features of the immune system.
Within a few years, several thousand biotech companies were founded in the U.S.
The industry went through successive waves of boom and bust; yet by 2005, nearly
1,500 biotech companies were active in the U.S.
The sequence from university spin-off to venture-capital-funded firm to publicly
traded company--pioneered so successfully by Genentech--was not followed
universally. For example, by the early 1980s, European countries and the U.S.
shared advanced capital markets, had well-educated scientists and physicians, and
had high-tech-based medical treatment. A biotechnology sector did not
immediately arise across Europe.
Whereas it made sense to speak of an American, German, French, or British drug
company as recently as a decade ago, mergers and greater cross-national R&D
investments have since rendered such delineation largely irrelevant. Between 1985
and 2005, nearly 40 major mergers produced firms of an unprecedented size and
scope in the pharmaceutical industry.
The scale of
PHARMA
WORLD ECONOMY
~$30.0T
US ECONOMY
~$11.0T
PHARMA:
0.4T
~$
1-2% of GLOBAL
ECONOMIC ACTIVITY
C1.2. Drug nomenclature
A drug usually has 3 names:
Chemical (化学名)
International Non-proprietary
names (INN, 通用名)
3. Commercial (商品名)
CH3
1.
2.
CH 3
H3C
O
OH
Chemical:
alpha-methyl-4-(2-methylpropyl)phenylacetic acid
Non-proprietary： Ibuprofen (布洛芬）
Commercial：
Advil, Advil Caplets, Advil, Children's, Cramp End,
Dolgesic, Excedrin IB, Excedrin IB Caplets, Genpril, Genpril Caplets, Haltran,
Ibifon 600 Caplets, Ibren, Ibu, Ibu-200, Ibu-4, Ibu-6, Ibu-8, Ibuprin, Ibuprohm,
Ibuprohm Caplets, Ibu-Tab, Medipren, Medipren Caplets, Midol IB, Motrin,
Motrin Chewables, Motrin, Children's, Motrin, Children's Oral Drops, MotrinIB, Motrin-IB Caplets, Motrin, Junior Strength Caplets, Nuprin, Nuprin
Caplets, Pamprin-IB, Q-Profen, Rufen, Trendar.
Chemical name:
Mostly following rules by Chemical Abstracts Service (CAS).
One compound can only have one name, and there is no confusion.
Commercial name:
Named by manufactures, one compound can have many different names, and
can be trade marked to protect the brand.
International non-proprietary names
Convenient to remember, needed when apply for registration, cannot be trade
marked or patented. One compound has only one name.
Discovery of New Drugs
Nature is still an excellent source of new drugs
(or precursors of new drugs).
Of the 20 leading drugs in 1999, 9 were derived
from natural products.
From 1983-1994 almost 40% of the 520 new
drugs approved were natural products or derived
from natural products.
60% of antitumor and anti-infective drugs are
natural products or derived from natural
products.