Organic Chemistry

1226 CHAPTER 30 The Organic Chemistry of Drugs

ORPHAN DRUGS

Because of the high cost associated with develop-

ing a drug, pharmaceutical companies are reluc-

tant to carry out research on drugs for rare diseases. Even if a

company were to find a drug, there would be no way to recoup

its expenditure, because of the limited demand. In 1983, the

U.S. Congress passed the Orphan Drugs Act. The act creates

public subsidies to fund research and provides tax credits for up

to 50% of the costs of developing and marketing drugs—called

orphan drugs—for diseases or conditions that affect fewer

than 200,000 people. In addition, the company that develops

the drug has four years of exclusive marketing rights if the drug

is nonpatentable. In the 10 years prior to the passage of this act,

fewer than 10 orphan drugs were developed. Today, there are

more than 100, and some 600 others are in development.

Drugs originally developed as orphan drugs include AZT (to

treat AIDS), (to treat ovarian cancer), Exosurf

(to treat respiratory distress syndrome in infants),

and Opticrom®(to treat corneal swelling).

Neonatal®

Taxol®

on new drugs. In addition, the average lifetime of a drug is only 15 to 20 years. After

that time, it is generally replaced by a newer and improved drug. Only about 1 in 3

drugs actually makes a profit for the company.

Why does it cost so much to develop a new drug? First of all, the Food and Drug

Administration (FDA) has very high standards that must be met before it approves a

drug for a particular use. Before the U.S. government became involved with the regu-

lation of drugs, it was not uncommon for charlatans to dispense useless and even

harmful medical preparations. Starting in 1906, Congress passed laws governing the

manufacture, distribution, and use of drugs. These laws are amended from time to time

to reflect changing situations. The present law requires that all new drugs be

thoroughly tested for effectiveness and safety before they are used by physicians.

An important factor leading to the high price of many drugs is the low success rate

in progressing from the initial concept to an approved product: Only 1 or 2 of every

100 compounds tested become lead compounds; out of a 100 structural modifications

of a lead compound, only 1 is worthy of further study; and only 10% of these

compounds actually become marketable drugs.

Summary

A drugis a compound that interacts with a biological mol-

ecule, triggering a physiological response. Each drug has a

proprietary namethat can be used only by the owner of

the patent, which is valid for 20 years. Once a patent ex-

pires, other drug companies can market the drug under a

generic namethat can be used by any pharmaceutical com-

pany. Drugs that no one wants to develop because they

would be used for diseases or conditions that affect fewer

than 200,000 people are called orphan drugs. The Food

and Drug Administration (FDA) has very high standards

that must be met before it approves a drug for a particular

use. The average cost of launching a new drug is about

$230 million.

The prototype for a new drug is called a lead com-

pound. Changing the structure of a lead compound is called

molecular modification. A random screen (or blind

screen) is a search for a pharmacologically active lead com-

pound without having any information about what structures

might show activity. The technique of relating a property of

a series of compounds to biological activity is known as a

quantitative structure–activity relationship (QSAR).

Many drugs exert their physiological effects by binding

to a specific cellular binding site called a receptor. Some

drugs act by inhibiting enzymesor by binding to nucleic

acids. Most antiviral drugsare analogs of nucleosides,

interfering with DNA or RNA synthesis and thereby

preventing the virus from replicating.

A bacteriostatic druginhibits the further growth of

bacteria; a bactericidal drugkills the bacteria. In recent

years, many bacteria have become resistant to all antibi-

otics, so drug resistancehas become an increasingly im-

portant problem in medicinal chemistry.

The therapeutic index of a drug is the ratio of the lethal

dose to the therapeutic dose. The higher the therapeutic

index, the greater is the margin of safety of the drug. The

effect of two drugs used in combination is called drug

synergism.

Large collections of compounds that can be screened for

biological activity are prepared by combinatorial organic

synthesis—the synthesis of a group of related compounds

by covalently connecting sets of building blocks.

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