The Unusual Discovery of Commonly Prescribed Medications: Part 3

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 1 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 1 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 were through serendipitous events. Part 2 of this article previously covered 5 medications.

11. Capoten (captopril)^3,4

Early descriptions of hypertension as a disease began to surface in the year 1808 although hypertensive symptoms have been described as early as in 10^th Century medieval medical texts. In 1975, captopril became the first ACE-inhibitor to be developed in the United States with its origin linked to an unusual source.

In the 1950s, researchers were focused on finding better treatment options for hypertension as therapy had consisted only of diuretics. During this time, the enzyme ACE was identified as being responsible for converting angiotensin I to the vasoconstrictor substance, angiotensin II, making it an exciting target for medication therapy. It was also known that there were reports of plantation workers in Brazil suddenly collapsing after being bitten by the pit viper, Bothrops jararaca, leading to drastic drops in blood pressure.

In 1968, studies conducted at the Royal College of Surgeons showed that peptides from the Brazilian viper’s venom inhibited the activity of ACE from the lungs of dogs. Pharmaceutical companies were initially skeptical about translating this to human use but eventually decided to pursue development of synthetic oral ACE inhibitors. Between 1970 and 1973, scientists at a pharmaceutical company now part of Bristol Myers Squibb tested approximately 2,000 chemical structures for ACE inhibitor activity without any noticeable breakthroughs. Following up on newly published research on pancreatic exopeptidases, they developed captopril with early clinical studies confirming its antihypertensive effects. Captopril formally gained FDA approval on April 6, 1981.

12. Chantix (varenicline)^5,6

Chantix is a nicotine receptor agonist used for smoking cessation whose history dates back to the 1940s. During World War II, leaves of the plant Cytisus laburnum were used by smokers as a tobacco substitute. The active substance, called cytisine, has a molecular structure that is similar to nicotine and works as a partial agonist at the nicotine receptor. Preliminary smoking cessation studies during the 1960s, however, failed to show significant benefit from cytisine, possibly due to poor absorption and limited CNS penetration.

As a result, Pfizer used cytisine as a starting point to develop a more potent and efficacious smoking cessation agent. One newly developed analog, varenicline, was brought to the market in 2006. Like cytisine, varenicline demonstrates partial agonism at the alpha-4-beta-2 nicotinic receptor, which is where nicotine has the highest binding affinity.

Notably, cytisine was approved as a smoking cessation drug in 2006 in Europe (branded as Tabex) but is currently unavailable in the United States.

13.Azilect (rasagiline)^7,8

In 1970, the Australian pharmaceutical company Aspro Nicholas filed a patent for a racemic version of rasagiline called AGN 1135. It was thought that this medication could be a viable therapy for treating hypertension as initial studies showed the compound lowered blood pressure after 2 weeks of therapy.

Around this time, an Iranian neuroscientist named Moussa Youdim starting experimenting with a similar drug called selegiline and discovered its MAO-B inhibitory properties could be beneficial in patients with Parkinson’s disease. In an attempt to find a similar medication with a better safety profile, Youdim started working with AGN 1135, which he simplified to the R-enantiomer, and named rasagiline.

Due to further studies confirming the anti-parkinsonian activity of rasagiline, the hypertension indication was dropped. It would later be approved by the FDA in 2006 for the treatment of Parkinson’s disease. Notably, rasagiline has a warning in its product labeling that it may actually cause hypertension (including severe hypertensive syndromes) at recommended doses.

14. Prozac (fluoxetine)^9,10

Prozac is a serotonin reuptake inhibitor (SSRI) indicated for the treatment of major depressive disorder, obsessive compulsive disorder, and panic disorder. With its approval in 1987, Prozac became the first major breakthrough for treating depression since the introduction of tricyclic antidepressants and monoamine oxidase inhibitors nearly 30 years earlier.

Synthesis of fluoxetine stemmed in part from the discovery of the antihistamine diphenhydramine in 1943. By the 1960s, research had shown that diphenhydramine inhibited reuptake of serotonin among interacting with a number of other receptors.

Researchers, in collaboration with the pharmaceutical company Eli Lilly, began experimenting with a compound that was structurally similar to diphenhydramine to develop a more specific serotonin reuptake inhibitor. After synthesizing a number of structural derivatives, researchers selected the most potent and selective molecule, later named fluoxetine.

15. Namenda (memantine)^11,12

Namenda is an NMDA receptor antagonist indicated for the treatment of moderate-to-severe dementia of the Alzheimer’s type. The memantine molecule was first synthesized and patented by Eli Lilly in 1968 as a potential medication to treat diabetes; however, it was found to be ineffective at lowering blood sugar. The NMDA activity was discovered in the late 1980s and it would later be approved by the FDA in 2003 for dementia. In 2014, memantine was coformulated with donepezil as Namzaric, for moderate to severe dementia.

Notably, there is some preliminary evidence that suggests memantine may be effective in treating diabetic neuropathy through its NMDA antagonism effects.

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.
• Heydari M, Dalfardi B, Golzari SE, Habibi H, Zarshenas MM. The medieval origins of the concept of hypertension. Heart Views 2014;15:96-8.
• Bryan J. From snake venom to ACE inhibitor - the discovery and rise of captopril. The Pharmaceutical Journal. 17 April 2009.
• Etter J. Cytisine for Smoking Cessation - A Literature Review and a Meta-analysis. Arch Intern Med. 2006;166(15):1553-1559. doi:10.1001/archinte.166.15.1553.
• Coe JW, Brooks PR, Vetelino MG, et al. Varenicline: an alpha4beta2 nicotinic receptor partial agonist for smoking cessation. J Med Chem. 2005 May 19;48(10):3474-3677.
• Riederer P, Laux G. MAO-inhibitors in Parkinson’s Disease. Experimental Neurobiology. 2011;20(1):1-17. doi:10.5607/en.2011.20.1.1.
• Lakhan SE. From a Parkinson’s disease expert: Rasagiline and the Future of Therapy. Molecular Neurodegeneration. 2007;2:13. doi:10.1186/1750-1326-2-13.
• Wenthur CJ, Bennett MR, Lindsley CW. Classics in Chemical Neuroscience: Fluoxetine (Prozac). ACS Chemical Neuroscience. 2014;5(1):14-23. doi:10.1021/cn400186j.
• Wong D, Bymaster F, Engleman E. Prozac (fluoxetine, Lilly 110140), the first selective serotonin uptake inhibitor and an antidepressant drug: twenty years since its first publication. Life Sci. 1995;57(5):411-441.
• Witt A, Macdonald N, Kirkpatrick P. Memantine hydrochloride. Nat Rev Drug Discov. 2004 Feb;3(2):109-10.
• Saad J, Petropoulos I, Alam U, Malik R. Treatment of painful diabetic neuropathy. Ther Adv Chronic Dis. 2015 Jan; 6(1): 15—28. doi: 10.1177/2040622314552071.