Molecules IF10, IF33 and IF41 resemble HMG CoA reductase structure (HMG-CoA-like residue) which is common in all three molecules. In the diagram above residue that is unchanged between all molecules is shown in red. It is also clear that three compounds also exhibit the same structure. However, the functional or side groups differ between all three, which explains the extent to which they inhibit cholesterol liver content. Molecule IF41 shows the most dramatic changes in cholesterol level due to fluorphenyl group attached to it which allows the compound to make more polar interactions and bind more tighter to the HMGR enzyme. Molecule IF33 stands the next in potency, however instead of fluorphenyl group it has hydroxyl group. Molecule IF10 has the smallest level of cholesterol lowering properties as it has the lowest molecular weight due to the absence of the ring structure attached to pyrimidine ring.
To increase the potency, polar methane sulfonamide group might be added to the pyrimidine ring instead of NH2 group to compound IF41 to increase unique polar interaction with the enzyme. The addition of that group would ultimately make it more potent if compared to other statins. Sulfur group might also be added. Ring that is attached to fluorphenyl group might be removed from the molecule. Instead of double bond interaction on the ring attached to pyrimidine ring (shown in green), dihydroxyheptenoic acid side chain could be added.
High Throughput Screen method to test the compounds would be based on a stable isotope dilution technique made by liquid chromatography with mass spectrometry. Product of HMG-CoA reductase would be converted from mevalonic acid to mevalonolactone in an incubation mixture, extracted then the derivativatised and purified. Resulting mevalonylamide would be quantified using the positive electrospray ionization mode. Thus, testing the potency of the compound.
Compund IF41 would reverdibly bind to the enzyme HMG-CoA reductase using its conformational flexibility that causes a shallow hydrophobic groove that IF41 would exploit in order to accommodate its hydrophobic moieties. HMG-CoA reductase is a rate limiting enzyme in the mevalonate pathway, by inhibiting the mevalonate production, consequently no cholesterol would be produced as it is one of the molecules in the cascade that eventualy produces cholesterol. Typical range of cholesterol reduction in these types of drugs varies between 30-60% depending on the amount administered, metabolism of the patient, route of administration, time of administration.
5/ In several experiments that were carried out in the past was concluded that combination therapy of Gemfibrasil and HMG-CoA reductase is more effective in reducing total cholesterol, low-density lipoprotein cholesterol, and triglycerides with a trend toward raising high-density lipoprotein cholesterol in patients with hyperlipidemia resistant to either agent alone. However, several case reports indicate that myositis and rhabdomyolysis do occur with combination therapy, un fortunately the incidence of these complications is not well defined. It is well known that HMG-CoA reductases alone may cause severe side effects such as muscle problems, increased risk of diabetes mellitus and liver damage, due to increased concentration of liver enzymes, neuropathy, pancreatic and liver dysfunction, and sexual dysfunction.
Therefore, if all factors would be taken in consideration, it would be safe to suggest that combinational therapy should be used only with patients who would not respond to IF41 or gemfibrozil alone in order to reduce the possibility of developing side effects.
6/ Due to increased healthcare and medical attendance for people in developed countries, life expectancy increases each year. Therefore, The global cholesterol-lowering drugs market is expected to grow at a CAGR of 4.9% in the first half of the forecast period. The market is estimated at $19.2bn in 2017. In the Statins and Fixed-Dose Combinations segment, Crestor was on the lead in 2016 and held a share of 26.7%. As it can be observed from the diagram, there is almost geometrical increase in the need/use of statins, therefore tremendous amount of money are being spent on the lipid lowering drug development in the recent years.
A number of statins are on the market: atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin Several combination preparations of a statin and another agent, such as ezetimibe/simvastatin, are also available. The newest ones, also called super statins, the third generation of this type of drug possesses remarkable potency and efficacy due to its fluorinated phenyl group and hydrophilic methane sulphonamide group in addition to the common dihydroxyheptenoic acid side chain. Super statins are now used in a high risk patients who more often develop statin intolerance.
In 2005, sales were estimated at US$18.7 billion in the United States. The best-selling statin is atorvastatin also known as Lipitor, which in 2003 became the best-selling pharmaceutical in history. The manufacturer Pfizer reported sales of US$12.4 billion in 2008. Due to patent expirations, several statins became available in 2016 as less expensive generics.
However on top of statin medicine, new type of drugs are emerging on the market (summarized in the table below).
Some of these drugs are;
1. Evolocumab, a fully human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9).
2. Ezetimibe, that works by impairing the body’s ability to absorb cholesterol in the gut
These drugs are relatively new and still under the trials, however the point that was noted for Evolocumab is that it would be too expensive which did not meet "generally accepted" cost-benefit annual cost of $4,500 would meet an acceptable $100,000 per QALY standard. It is made by Amgen.
Taking all these points into consideration, such as incredibly competitive market and newest compounds that in a couple decades may replace statins, it would not be worth competing for the market.