that produce an adverse effect on the fetus. Toxicity problems have resulted in
many drugs being withdrawn from the market, as shown in table 3.3. As shown in
figure 3.11, toxicity problems are a major cause of drug rejection during the develop-
ment process.
Successful completion of the four phases of human clinical trials enables a drug to
be widely distributed for the treatment of human disease. However, a simple reality of
drug discovery is that drugs are developed by industry. The lead compound may have
been identified in an academic university-based laboratory, but the clinical trials are
invariably completed by the industrial sector. Academic institutions, governments, or
international organizations (e.g., the World Health Organization, WHO) do not develop
drugs. Because of this, drug molecules tend to be developed only if they have a good
prospect for being profitable. In order to be profitable, a drug molecule should be
patented so that the vendor can enjoy exclusive rights to its marketing. Although a
discussion of the criteria for patentability is beyond the scope of this book, the drug
162 MEDICINAL CHEMISTRY
Table 3.3Approved Drugs Withdrawn Because of Toxicity
Drug Year Adverse reaction
Astemizole 1998 Interactions (e.g., with grapefruit juice)
Benoxaprofen 1982 Liver damage
Centoxin 1993 Increased mortality
Cerivastatin 2001 Muscle breakdown
Cisapride 2000 Cardiac arrhythmias
Clioquinol 1975 Optic neuropathy (eye problem)
Dexfenfluramine 1997 Cardiac valve abnormalities
Fenfluamine 1997 Cardiac valve abnormalities
Flosequinan 1993 Increased mortality
Indoprofen 1984 Gastrointestinal bleeding/perforation
Metipranolol 0.6% eyedrops 1990 Anterior uveitis (eye problem)
Mibefradil 1998 Many drug interactions
Nomifensine 1986 Hemolytic anemia
Noscapine 1991 Gene toxicity
Remoxipride 1994 Aplastic anemia
Sertindole 1998 Cardiac arrhythmias
Suprofen 1987 Renal impairment
Temafloxacin 1992 Various serious adverse effects
Terodiline 1991 Cardiac arrhythmias
Tolcapone 1998 Hepatobiliary disorders
Triazolam 1991 Psychiatric disorders
Troglitazone 1997 Hepatic disorders
Zimeldine 1983 Hypersensitivity
Zomepirac 1983 Anaphylaxis