Discovery and development of statins trials showed very good inhibitory effect as in clinical trials, however in a long term toxicity study in dogs it resulted in toxic effects at higher doses and as a result was believed to be too toxic to be given to humans. In 1978, Alfred Alberts and colleagues at Merck Research Laboratories discovered a new natural product in a fermentation broth of "Aspergillus terreus", their product showed good HMGR inhibition and they named the product mevinolin, which later became known as lovastatin. The cholesterol controversy began in the early promotion of statins. Statins are a competitive antagonists of HMG CoA,
Discovery and development of statins that the statins exploit and is used to accommodate their hydrophobic moieties. The specificity and the tight binding of statins is due to orientation and bonding interactions that form between the statin and the HMGR enzyme. Polar interactions are formed between the HMG-moiety and residues that are located in the cis loop of the enzyme. These polar interactions are between Ser, Asp, Lys and Lys (Figure 4). The terminal carboxylate of the HMG moiety forms a salt bridge with the cationic Lys of the enzyme. In addition to the polar interaction, Lys participates in a hydrogen bonding network with Glu,