Medicinal Chemistry

Faculty member in charge: Professor (Penny Yu) 于沛

Other participating facultymembers: 王玉强 , 陈卫民 , 陈河如

Lecture time: Fall, 2009

College: 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 GLOBALECONOMIC ACTIVITY

C1.2. Drug nomenclature

A drug usually has 3 names:

1. Chemical ( 化学名 )2. International Non-proprietary

names (INN, 通用名 )3. Commercial ( 商品名 )

Chemical: alpha-methyl-4-(2-methylpropyl)phenylacetic acidNon-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, Motrin-IB, Motrin-IB Caplets, Motrin, Junior Strength Caplets, Nuprin, Nuprin Caplets, Pamprin-IB, Q-Profen, Rufen, Trendar.

CH3

OHCH3

H3C

O

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 DrugsNature 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.