Case Histories of Drug Discovery
Every drug has a unique story on its journey from an idea to the marketplace. What is almost always the case though is that each drug has a champion, to help guide the concept and the drug compound through sometimes difficult waters. Nowadays, a company will often be completely reorganized, change management or be acquired by a competitor several times during the period when a promising compound is in late stage discovery or development. There are a number of marketed drugs, including Buspirone, Prozac, Acyclovir or Viagara that may not have come to light in modern laboratories. Too often we try to over-organize research, and serendipitous events do not occur as often. A measured but urgent environment where inventions can prosper should be sought so scientists can “make their own luck”! Lars has recently had a review on this topic called “Drug Discovery Management: Small is Still Beautiful: Why a Number of Companies Get it Wrong” accepted by the Elsevier journal Drug Discovery Today, which will be published in early summer 2011.
The drugs listed were invented by scientists relying often on instinctive invention and observation, who sometimes fought shy of formal systems. Many drugs are the product of serendipity, or “lucky” observations, but in fact the scientists involved often “made their own luck”, by acting on seemingly disparate data to hunt for a new disease treatment.
Buspirone – was designed as a selective 5HT1A receptor agonist, but only emerged as a novel treatment for anxiety when it was in late stage preclinical development and it was dosed to primates, which were much less alarmed and anxious when their cages were literally rattled. This effect had not been observed in rodents, and is explained by the presence of a hydroxyl metabolite of the parent drug that is only observed in primates and humans. The drug, marketed by Bristol Myers Squibb went on to achieve a turnover of over $500M per annum.
The discovery of Prozac was an early example of rational drug design. In the late 1960s, Bryan B. Molloy and Klaus K. Schmiegel, chemists at Eli Lilly & Co. in Indianapolis, began synthesizing compounds based on the antihistamine Benadryl (diphenhydramine), which has some anxiolytic/ and antidepressant properties. A Lilly colleague, David T. Wong, tested these new compounds and found that one – with a -CF3 in the phenyl para-position – blocked uptake of serotonin and apparently very little else. In 1974, the team publicly announced their discovery, and later clinical trials proved fluoxetine – soon branded as Prozac – to be effective in the treatment of depression and to lack the significant side effects of its predecessors. The drug was not launched until 1986, giving evidence of a long development time; Prozac was apparently “on hold” for long periods, often a fate for an ultimately successful first-in-class drug.
The reasons for Acyclovir’s (ACV) activity and selectivity in cells infected with Herpes Simples Virus (HSV) or Varicella Zoster Virus (VZV) are summarized as: 1. Activation by a HSV- or VZV-specified Thymidine kinase, forming a phosphate ester. 2. The viral DNA polymerase has a greater sensitivity than the cellular polymerases to the resultant triphosphate. 3. Inactivation of the viral DNA polymerase, but not the cellular polymerases, by ACV-TP. 4. Chain termination of viral DNA by incorporation of ACV-MP. The team under eventual Nobel Prize winner Gertrude Elion at Burroughs Wellcome built these theories on the observation that ACV possessed in vitro antiviral activity, but apparently the initial observation was made serendipitously; the compound may have been tested in the antiviral assay unintentionally.
Viagara was a Phosphodiesterase V inhibitor in clinical trials for cardiovascular disorders including angina pectoris, and invented by my friend Dr. Nick Terrett, a former colleague from Glaxo, Ware, UK. However, notable side-effects were observed during a hospital trial, and the drug was developed for treatment of erectile dysfunction; the rest is history!
The accounts mentioned above shows how every drug is unique; but scientists need to have time and space as well as the motivation to observe and discover, “making thir own luck” by sound observation. The invention and development of a new drug rarely follows a prescribed pattern. This was certainly the case at Vernalis with the early stages of the discovery of the A2A antagonist Vipadenant V2006/BIIB0014, which has shown PoC in Parkinson’s Disease; the early lead structure came from investigating the CNS side-effects of the antimalarial drug Mefloquine. The (-)-enantiomer of this compound turned out to have adenosine A2A receptor affinity. When I wrote the project proposal in 1999 while at Vernalis PLC, I was not aware how the medicinal chemists working in my team would eventually evolve the structure through iterative optimization to provide the triazolopyrimidine drug candidate V2006.
The discipline of drug-hunting requires an openness to new thinking, determination, teamwork and an ability to link apparently disparate observations into a novel rationale. Unique management skills are required to provide the right environment for these amazing discoveries to prosper for the benefit of mankind and the companies sponsoring the research work.