Drug Discovery and Development. How are drugs discovered and developed?. Basic Steps. Choose a disease Choose a drug target Identify a “bioassay” bioassay = A test used to determine biological activity. Find a “lead compound”
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How are drugs discovered and developed?
bioassay = A test used to determine biological activity.
“lead compound” = structure that has some activity against the chosen target, but not yet good enough to be the drug itself.
pharmacophore = the structural features directly responsible for activity
pharmacokinetic = The study of absorption, distribution, metabolism and excretion of a drug (ADME).
In vitro testing
In vivo tests
Screening Natural Products
Screening synthetic banks
Using Someone Else’s Lead
Enhance a side effect
Use structural similarity to a natural ligand
Computer-Assisted Drug Design
Serendipity: a chance occurrence
Sildenafil (compound UK-92,480) was synthesized by a group of pharmaceutical chemists working at Pfizer's Sandwich, Kent research facility in England. It was initially studied for use in hypertension (high blood pressure) and angina pectoris (a form of ischaemic cardiovascular disease). Phase I clinical trials under the direction of Ian Osterloh suggested that the drug had little effect on angina, but that it could induce marked penile erections. Pfizer therefore decided to market it for erectile dysfunction, rather than for angina. The drug was patented in 1996, approved for use in erectile dysfunction by the Food and Drug Administration on March 27, 1998, becoming the first pill approved to treat erectile dysfunction in the United States, and offered for sale in the United States later that year. It soon became a great success: annual sales of Viagra in the period 1999–2001 exceeded $1 billion.
RH + O2 + 2H+ + 2e– → ROH + H2O
Thalidomide was developed by German pharmaceutical company Grünenthal. It was sold from 1957 to 1961 in almost 50 countries under at least 40 names. Thalidomide was chiefly sold and prescribed during the late 1950s and early 1960s to pregnant women, as an antiemetic to combat morning sickness and as an aid to help them sleep. Before its release, inadequate tests were performed to assess the drug's safety, with catastrophic results for the children of women who had taken thalidomide during their pregnancies.
Antiemetic = a medication that helps prevent and control nausea and vomiting
From 1956 to 1962, approximately 10,000 children were born with severe malformities, including phocomelia, because their mothers had taken thalidomide during pregnancy. In 1962, in reaction to the tragedy, the United States Congress enacted laws requiring tests for safety during pregnancy before a drug can receive approval for sale in the U.S.
Phocomelia presents at birth very short or absent long bones and flipper-like appearance of hands and sometimes feet.
Researchers, however, continued to work with the drug. Soon after its banishment, an Israeli doctor discovered anti-inflammatory effects of thalidomide and began to look for uses of the medication despite its teratogenic effects. He found that patients with erythema nodosum leprosum, a painful skin condition associated with leprosy, experienced relief of their pain by taking thalidomide. Further work conducted in 1991 by Dr. Gilla Kaplan at Rockefeller University in New York City showed that thalidomide worked in leprosy by inhibiting tumor necrosis factor alpha. Kaplan partnered with Celgene Corporation to further develop the potential for thalidomide. Subsequent research has shown that it is effective in multiple myeloma, and it is now approved by the FDA for use in this malignancy. There are studies underway to determine the drug's effects on arachnoiditis, Crohn's disease, and several types of cancers.
Teratogenic = Causing malformations in a fetus