Medicinal Chemistry

Phase 3 — the drug is studied in a large number of people (hundreds to thousands)

who have the disease under study, typically using a multi-center, double-blind,

placebo–controlled, randomized clinical trial (RCT) protocol.

Phase 4 — once the drug has been approved for market, vigilant post-marketing sur-

veillance is done to ascertain the possible appearance of previously undetected tox-

icities or problems.

The drug development process is long, as is shown in figure 3.10. During the drug
development phases, toxicity is one of the most important hurdles to the success of a
drug molecule. Toxicity can affect the person who is taking the medication (causing
skin rashes, liver problems, bone marrow failure, etc.) or, in the case of women,
can affect their developing fetus if they are pregnant. Table 3.2 lists some of the drugs

DESIGNING DRUG MOLECULES TO FIT RECEPTORS 161

Table 3.2 Drugs Producing Adverse Effects on the Fetus

Drug Effect

ACE inhibitors Kidney damage
Amphetamines Abnormal developmental patterns
Androgens Masculinization of female
Busulfan Congenital malformations
Carbamazepine Neural tube defects affecting brain formation
Cocaine Stroke in fetus
Cyclophosphamide Congenital malformations
Cytarabine Congenital malformations
Diethylstilbestrol Vaginal adenocarcinoma in child
Ethanol Risk of fetal alcohol syndrome
Etretinate High risk of multiple congenital malformations
Iodine Congenital goiter, hypothyroidism
Isotretinoin High risk of face, ear, and other malformations
Methotrexate Multiple congenital abnormalities
Methylthiouracil Hypothyroidism in child
Metronidazole May be mutagenic (animal studies show no evidence for
mutagenic or teratogenic effects in humans)
Penicillamine Congenital skin malformations
Phenytoin Fetal hydantoin syndrome
Propylthiouracil Congenital goiter
Streptomycin Eighth nerve toxicity (deafness) in child
Tamoxifen Increased risk of spontaneous abortion or fetal damage
Tetracycline Discoloration and defects of teeth and altered
bone growth
Thalidomide Phocomelia (shortened bones of the limbs)
Trimethadione Multiple congenital abnormalities
Valproic acid Neural tube defects of the brain