Natural products cardiovascular drug leads

The study of natural products, or Nature s Combinatorial Library , has had a long history as a source of drugs, and plants have historically been at the forefront of natural product drug discovery. In the anticancer area, for example, vinblastine and vincristine, etoposide, paclitaxel (Taxol), docetaxel, topotecan, and irinotecan, among others, are all plant-derived natural products or modified versions of plant compounds, while antimalarial therapy would be much poorer without quinine and artemisinin and the drugs derived from these plant products. This chapter provides an overview of the major medicinal agents that are themselves natural products isolated from plants or are chemical modifications of such lead compounds. It covers the therapeutic areas of cancer, HIV, malaria, cardiovascular, and central nervous system (CNS) diseases. Natural plant products have also made contributions in areas such as immunomodulatory and antibiotic activities," and the reader is referred to the cited reviews for information on these areas. 

Millions of people in the world suffer from cardiovascular disease, and it is a leading cause of death in both men and women. Elevation in plasma low-density lipoprotein (LDL) cholesterol levels is a major risk factor for myocardial infarction (heart attack) in these patients. Drugs to reduce dyslipidemia have included niacin and the fibrate class, but each of these has clinical limitations, such as low efficacy or toxic side effects. The development of HMG-CoA reductase inhibitors, or statins, has had an enormous clinical impact on the treatment of heart disease and prevention of heart attack, and these are taken by tens of millions of patients worldwide [1]. One of the first such drugs, lovastatin, was discovered in the 1970s as a fungal natural product [2] and lowered lipid levels in animals and healthy volunteers. Problems with the development of another early statin, compactin, halted advancement of lovastatin to regular clinical use until the late 1980s. Since then. 

The influence of natural products in the discovery of new marketed therapeutics continues to be significant in various therapeutic areas. Burger s Medicinal Chemistry and Drug Discovery reviews natural products as leads for new pharmaceutical products for the central nervous system, neuromuscular disease, cancer, bacterial infections, cardiovascular disease, asthma, and parasites. Dmgs such as morphine, penicillin, cyclosporine A, lovastatin, acarbose, FK506 (tacrolimus), and pachtaxel (Taxol )... 

Unlike the well-described cysteine proteases cathepsin S (CatS) and cathepsin L (CatL), the serine protease cathepsin A (CatA) is less well known in the scientific community as a potential drug target. We became aware of pharmacological studies conducted during the 1990s with the natural product ebelactone B [1]. These studies postulated therapeutic benefits in cardiovascular diseases after CatA inhibition. Based on these reports, we started our own research program for small-molecule inhibitors of CatA and we published some of oiu" results in two research articles [2,3]. In this chapter, we will provide the reader with an in-depth discussion of our lead discovery strategy and include a siunmary of our results. 

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