The Unusual Discovery of 10 Commonly Prescribed Medications: Part 1

The process of drug discovery and testing can be a long, slow, and painful road. It’s estimated that for approximately every 10,000-15,000 new compounds identified, only 5 will be considered safe for testing in human volunteers and one will be approved by the FDA.¹ Additionally, the journey from preclinical studies to FDA approval can take 10-15 years and range in cost from $800 million to $1.4 billion.

There are many factors that contribute to the process of drug discovery. One particular phenomenon that has been described in the literature involves serendipity, or chance discovery (i.e. finding one thing while looking for another). According to one analysis, serendipitous events were identified in the discovery of nearly 6% of all drugs in use today.²

This article will describe the unusual discovery of 5 commonly prescribed medications, many of which occurred through serendipitous events.

1. Sildenafil (Viagra)³

In the late 1980s, scientists at Pfizer sought to develop a drug that could treat angina, similar to nitrates, but lack any tolerance effects. They hypothesized that blocking the enzyme PDE5 (phosphodiesterase type 5) could lead to vasodilation and treat angina. By the early 1990s, Pfizer began experimenting with a compound known as UK-92480 (later renamed sildenafil); however, researchers soon discovered the drug had a relatively short half-life and a potentially dangerous interaction of lowering blood pressure when used in combination with nitrates.

During phase 1 trials, it was noted that while the drug had little effect on angina, men began reporting erections as an unintended side effect. Pfizer decided to instead market the medication for erectile dysfunction after further studies showed benefit in this group. In 1998, Viagra became the first FDA approved oral medication for the treatment of erectile dysfunction. Seven years later, sildenafil was approved as Revatio for the treatment of pulmonary arterial hypertension (PAH).

2. Librium (chlordiazepoxide)⁴

Chlordiazepoxide is a benzodiazepine that is FDA approved for the management of anxiety and withdrawal symptoms from acute alcoholism. It was the first benzodiazepine developed and served as a prototype for future compounds.

Synthesis of chlordiazepoxide is credited to a New Jersey pharmacist and chemist named Leo Sternbach. In the 1930s Sternbach created several heptoxdiazine compounds in an effort to develop synthetic dyes. Two decades later, he resumed research with his heptoxdiazine compounds after being inspired by the success of the 2 psychotropic drugs, chlorpromazine and meprobamate, and in an effort to find safer alternatives to barbiturates.

During his research, Sternbach started to synthesize multiple derivatives of compounds that he discovered were not heptoxdiazines, but rather benzoxadiazepines. Initially, most of these were tested and found to be pharmacologically inert. One particular compound was stabilized using methylamine but it remained on his shelf until 1957 when it was discovered during a laboratory cleanup. The drug was tested and found to be biologically active and a strong CNS depressant. The structure of this compounded was identified as 1,4-benzodiazepine and named chlordiazepoxide. It was introduced into clinical use in 1960 followed by Valium (diazepam) in 1963.

3. Coumadin (warfarin)^5,6

Warfarin is a vitamin K antagonist used to treat blood clots and prevent stroke in high risk individuals. The history of warfarin dates back to the early 1920s when cattle in the northern United States and Canada became afflicted by an outbreak of a previously unrecognized disease that resulted in fatal internal bleeding. It was soon discovered that the cattle were ingesting moldy silage made from sweet clover hay, which was shown to contain a hemorrhagic factor that reduced the activity of prothrombin. Ten years later, scientists in Wisconsin identified that the anticoagulant in the sweet clover was a derivative of coumarin.

Further research was conducted to synthesize various coumarin derivatives. In 1952, one was approved as rodent poison in hopes of developing “better mousetraps.” Several years later attention shifted to human use after scientists identified that warfarin had a number of favorable chemical properties. At the time, anticoagulants such as heparin had to be given intravenously while others had a long onset to action.

In 1955, warfarin was given to President Dwight Eisenhower following a myocardial infarction. As one author pointed out “what was good for a war hero and the President of the United States must be good for all, despite being a rat poison!” Further clinical studies would later be conducted to reaffirm the clinical benefit of warfarin as a blood thinner in humans. Notably, the name warfarin is derived from WARF (Wisconsin Alumni Research Foundation) and -arin from coumarin.

4. Digoxin (Digox)^7,8

Digoxin is a cardiac glycoside that is used to increase contraction of the heart in patients with congestive heart failure and atrial fibrillation. Digoxin comes from the foxglove plant, digitalis purpurea, and has been described in writings as early as the year 1250.

The first medical report of digoxin dates back to 1785 when William Withering, an English physician and botanist, published An Account of the Foxglove and some of its Medical Uses. In his book, he described an account of a patient who visited him several years prior with a bad heart condition that he was unable to treat. The patient subsequently went to a local folk herbalist and experienced significant improvement after taking a secret herbal tea containing more than 20 ingredients.

Withering identified the active ingredient as digitalis and started testing different formulations in his heart failure patients. In the 1877 book, Neale's Medical Digest, the author explains that at the time, digitalis was being prescribed for over 32 medical conditions including adenitis, bronchitis, tuberculosis, and typhoid.

5. Topamax (topiramate)^9,10

Topiramate is an anti-epileptic drug that was FDA approved in 1996 to treat seizures and in 2004 for migraine prevention. Originally, topiramate was discovered as an oral hypoglycemic agent for diabetes. It was later found to be more effective for treating seizures and its role in diabetes was abandoned.

More recent evidence, however, suggests that topiramate has properties that may make it valuable in the treatment of diabetes. In animal models, it has been shown to act as both an insulin secretagogue and sensitizer. Some experts have argued that in humans, most of the effect of topiramate in diabetes is likely from to its ability to result in weight loss. Notably, topiramate is co-formulated with phentermine as Qsymia for chronic weight management.

References:

• About Drug Development Process. PPD. Available at: http://www.ppdi.com/About/About-Drug-Discovery-and-Development. Accessed May 17, 2017.
• Hargrave-Thomas E, Yu B, Reynisson J. Serendipity in anticancer drug discovery. World J Clin Oncol 2012; 3(1): 1-6.
• Ghofrani HA, Osterloh IH, Grimminger F. Sildenafil: from angina to erectile dysfunction to pulmonary hypertension and beyond. Nat Rev Drug Discov. 2006 Aug;5(8):689-702.
• Ban T. The role of serendipity in drug discovery. Dialogues Clin Neurosci. 2006 Sep; 8(3): 335—344.
• Pirmohamed M. Warfarin: almost 60 years old and still causing problems. Br J Clin Pharmacol. 2006 Nov; 62(5): 509—511. doi: 10.1111/j.1365-2125.2006.02806.x.
• Wardrop D, Keeling D. The story of the discovery of heparin and warfarin. Br J Haematol. 2008 Jun;141(6):757-63. doi: 10.1111/j.1365-2141.2008.07119.x. Epub 2008 Mar 18.
• Norn S. Kruse PR. Cardiac glycosides: From ancient history through Withering's foxglove to endogeneous cardiac glycosides. Dan Medicinhist Arbog. 2004:119-32.
• Digitalis purpurea. Texas A&M University Bioinformatics Working Groups. Available at: http://botany.csdl.tamu.edu/FLORA/Wilson/481/medbot/bot2.htm. Accessed May 15 2017.
• Arnone D. Review of the use of Topiramate for treatment of psychiatric disorders. Annals of General Psychiatry. 2005;4:5. doi:10.1186/1744-859X-4-5.
• Khanna V, Arumugam S, Roy S, Mittra S, Bansal VS. Topiramate and type 2 diabetes: an old wine in a new bottle. Expert Opin Ther Targets. 2008 Jan;12(1):81-90.