Cyclosporines discovery

The discovery of oxazoline hydroxamates as potential inhibitors of LpxC was the result of high-throughput screening of large libraries of compounds at the Merck Research Laboratories in collaboration with the Department of Biochemistry, Duke University Medical Center [95]. The lead compound, L-573,655, was a racemic mixture of 4-carbohydroxamido-2-phenyl-2-oxazoline, which had been previously made by Stammer et al. [96] as a precursor in the chemical synthesis of cyclosporine. Namely, (R,S)-serine methyl ester hydrochloride (149) is converted into (R,S)-4-carbomethoxy-2-phenyl-2-oxazoline (150) via treatment with ethyl benzimidate using the Elliot procedure [97]. Treatment of this ester with one equivalent each of hydroxylamine and sodium methoxide in methanol at room temperature affords the desired (R,S)-4-carbohydroxamido-2-phenyl-2-oxazoline (151), as depicted in Scheme 30. 

Borel JF. (2002) History of the discovery of cyclosporin and of its early pharmacological development. Wien Klin Wochenschr 114 433 37. 

A new era in the development of immunopharmacology began with the discovery of cyclosporines. 

The immimosuppressive effect of cyclosporin and FK506 could not initially be explained by these observations. Only with the discovery that cyclosporin and FK506 achieve their immunosuppressive effect via inhibition of calcineurin did it become clear that the immimosuppression is mediated by a complex reaction chain involving calcineurin. It was shown that the complexes of cyclosporin/cyclophilin and FK506/ FK506 binding protein bind to calcineurin and inhibit the phosphatase activity of the latter. 

Originally developed for chemotherapy, azathioprine is used today mainly as an immunosuppressive agent and rarely as an antineoplastic drug. It was introduced as an immunosuppressive agent by a British pioneer of tissue transplantation, Roy Caine. Azathioprine was used to prevent rejection after tissue transplantation as a replacement for 6-mercaptopurine because it was less toxic. In addition to tissue transplantation, it is also used for rheumatoid arthritis and Crohn s disease. Azathioprine is a prodrug which in the body is converted to its active metabolites 6-mercaptopurine and 6-thioinosinic acid. Until the discovery of cyclosporine, azathioprine in combination with steroids was the standard treatment to prevent rejection after tissue transplantation. 

Ancient mythology and biblical references mention heart transplantation, but after the initial work of Alexis Carrel in the early 1900s, dog heart transplants were performed at Mayo Clinic in 1933. The work of Norman Shumway at Stanford University, reported in 1959, led to the first human transplant by Christian Bernard in 1967 in South Africa. By the 1970s, the enthusiasm diminished due to poor survival rate after heart transplantation until the discovery of cyclosporine. 

Natural products have served as a major source of drugs for centuries, and about half of the pharmaceuticals in use today are derived from natural products. Quinine, theophylline, penicillin G, morphine, paclitaxel, digoxin, vincristine, doxorubicin, cyclosporin, and vitamin A all share two important characteristics they are cornerstones of modem pharmaceutical care, and they are all natural products. The use of natural substances, particularly plants, to control diseases is a centuries-old practice that has led to the discovery of more than half of all modem pharmaceuticals. 

Immunosuppressants, such as FK506, repamycinans cyclosporine A (CsA), attracted intensive research interests during the late 1980s and early 1990s,3233 with the aim to understand the mechanism of action.34 Renewed interest in these compounds developed from the discovery that some of the compounds, such as FKBP-12, have the potential to penetrate the blood-brain barrier and have also demonstrated a capacity for nerve regeneration activity. 

Just a few years after the discovery of cyclosporin, another major fiingal-derived drug was identified, namely lovastatin or mevinolin (Figure 9). Introduced by Merck to treat hypercholesterolemia, lovastatin was the forerunner of a family of lipid lowering drugs, the "statins", currently occupying over 80% of this 8 billion market. 

With the discovery and development of cyclosporine, a new era in immunopharmacology was born. Cyclosporine was the first agent to affect a specific cell line of the body s immune defenses. It is suppressive mainly to T cells, in condast to the cytotoxic agents, which affect all cell lines at the same time. Cyclosporine is the forerunner of a group of immunosuppressants that are acdve against specific components of the immune response. 

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