Cardiovascular diseases (CVDs) remain the number one cause of death globally [1], some key risk factors for CVD include hypertension, diabetes and hyperlipidemia (i.e. high cholesterol). While cholesterol is essential for the proper structure and function of all animal cell plasma membranes, high levels of blood cholesterol has proven to be a serious contributor to CVD and mortality.
Francois Poulletier was the first to purify cholesterol from gallstones in 1758 and 13 years later a French chemist Michel E. Chevreul named it cholesterine (solid bilein Greek:cholefor bile andstereosfor solid) [2,3]. During the 19th century, arteriosclerosis (the stiffening of the arteries) was recognized, however its pathological significance was not well established. In 1910 it was reported that atherosclerotic plaques contained over 20-fold higher cholesterol concentrations than did normal aortas [4]. Later, a Russian pathologist fed pure cholesterol to rabbits and produced the first experimental model of atherosclerosis via hypercholesteremia (high cholesterol in the blood) [5]. Emerging clinical interest foreshadowed the rigorous effort in the 1950s to unravel the pathway of cholesterol synthesis in the body and the major outlines of this pathway were completed by the 1960s by Konrad Bloch and Feodor Lynen [6–8]. When these scientists were awarded the Nobel prize in 1964, the following statement was declared: “Your discoveries may provide us with weapons against some of mankind’s gravest maladies, above all in relation to cardiovascular diseases. Achievements like yours make it not unrealistic to look forward to a time, when mankind will not only live under vastly improved conditions but will itself be better” [5]. They had no way of knowing it at this time, but the weapons that would be provided from this knowledge would soon be discovered and named statins, which would be among the most widely prescribed medications globally.
Mevastatin (compactin)
As with most pharmacological breakthroughs in the early stages of medicine, the discovery of the original statin was a process of rigorous trial and error with natural isolated products as opposed to the highly target-focused synthesis of today’s common fully synthetic drugs. It was a biochemist by the name of Akira Endo who had a history in working with mushrooms and other molds who speculated that these fungi would produce antibiotics that inhibited the enzyme HMG-CoA reductase, a key element in the cholesterol synthesis pathway. In 1973, he had found three active entities that were potent in inhibiting cholesterol synthesis [9–11], the most active was termed ML-236B isolated fromPenicillium citinuium and was later referred to as compactin. This was essentially the first drug in the statin class and would be the blueprint compound for subsequent synthetic and semi-synthetic statins. Compactin acts to lower the production of cholesterol in the liver by competitively inhibiting HMG-CoA reductase with a binding affinity 10,000x that of HMG-CoA itself [12]. Importantly, when liver cholesterol levels are decreased this causes an increased removal of cholesterol in blood circulation. Unfortunately, although this sounds like the idealistic compound for the task of lowering blood cholesterol, compactin had some detrimental side effects related to severe muscle abnormalities [11]. It was these detrimental properties which would lead to the discontinuation of compactin as a prospective clinical therapeutic.
Figure 1. Statin Schematic. Statins work by competitively inhibiting the HMG CoA reductase enzyme to prevent the production of cholesterol in vivo. Note that this is an oversimplification along the cholesterol synthesis pathway. Created with BioRender.com
Atorvastatin (Lipitor)
Science and the pharmaceutical industry have made tremendous progressions since the discovery of the first statin, compactin. However, there is remarkably not much of a difference between modern statins such as Lipitor compared to compactin at a mechanistic level. Notably though, Lipitor is one of the four currently available fully synthetic statins5. This means that it was not isolated from a naturally occurring organism/bacteria and was fully designed in-house at Pfizer. Lipitor acts as a competitive inhibitor of HMG-CoA reductase, much like that of compactin, however it does not have as high of a risk for the muscle abnormalities associated with compactin [13]. In 2017, Lipitor was the second most prescribed medication in the U.S. with >104 million prescriptions [14]. A key contributing factor to its success as a therapeutic is its convenient tablet formulation due to its rapid absorption following oral administration along with its 14-hour half-life meaning its therapeutic effect lasts for a long time and only needs to be taken once a day. The current spectrum of statins available in the U.S. consists of 7 different drugs and the patient prescription depends on patient characteristics and risks for adverse effects. Drug-drug interactions are a higher risk for some statins than others and should also be considered if a patient is taking other medications.
Conclusions
The work done by Bloch and Lynen to outline the pathway of cholesterol synthesis, and the subsequent dedication of Akira Endo to isolate a competitive inhibitor of HMG-CoA reductase equipped us today with statins as a weapon against cardiovascular disease. Although research efforts will always look for the development of new drug classes with new mechanisms, improvements of current classes are also a vast area of research meaning that it is possible new and improved statins will be introduced to the market in the future.
References
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