next 30 years a number of related drugs, such as phenylephrine and isoprenaline, were introduced as therapeutic agents (Figure 10.1). The identification of a- and p-adrenergic receptor subtypes by Ahlquist in 1948 opened further therapeutic opportunities, first realized in the development of antagonists for the a-adrenergic receptor, such as phentolamine, tolazoline, and prazosin, and for the p-adrenergic receptor, propranolol. When p-adrenergic receptors were divided into pj, p2, and p3 subtypes, salbutamol emerged in 1967 as the first agonist with selectivity for the p2 receptor, while metoprolol and atenolol were introduced later as selective antagonists for the pj receptor. Many drugs that were used therapeutically throughout the twentieth century, and currently, were discovered through the same or similar approaches.

Following these discoveries, additional medicines were obtained by modification of native forms of natural products. The initial success of the antibiotic penicillin as an antiinfective was followed quickly by the emergence of resistance, which in turn led medicinal chemists to modify the molecule to produce new, semisynthetic drugs with improved resistance profiles. During the 1960s and 1970s, the pharmaceutical industry focused major efforts on screening natural products both as extracts and in pure form, and through these efforts cephalo-sporins such as cefuroxime, aminoglycosides such as streptomycin, and polyenes such as amphotericin B were obtained. The discoveries of the anticancer agent, paclitaxel, of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase

Figure 10.1 Chronology of drug innovation.

antilipid inhibitors such as atorvastatin derived from 3-hydroxycompactin, and of the immunosuppressant, FK506/tacrolimus, were additional triumphs of these efforts. In each of these instances, synthetic chemistry was used to improve the therapeutic efficacy and safety of the original, naturally occurring molecule.

In recent years, however, interest in natural products has waned and libraries of synthetic molecules have tended to replace them as the primary resource of chemical screens for new drugs.8 Between 1981 and 2003 only 5% of 1031 new chemical entities approved by the Food and Drug Administration (FDA) were natural products while another 23% were derived from natural product molecules. However, these newer sources supplied fewer good leads than expected, and today there is a resurgence of interest in natural products obtained from marine organisms, rain forests, and soil as the search intensifies for targets identified via genetic technologies. Certainly, natural products are still major sources of innovative therapeutics and have proven useful as drugs or as leads as shown by vancomycin in the treatment of Gram-positive bacterial infections, by stauros-porine as a lead structure for the inhibition of protein kinases at the ATP-binding site, by rapamycin as a lead for immunosuppression, and by Taxol for cancer chemotherapy. Even though the complexity of many natural products is a barrier to optimize their therapeutic use, the increasing efficiency of synthetic bioorganic chemistry is reducing this barrier, even for substances with very complex


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