Classical Drug Research

Although the era of classical drug discovery was based heavily on trial and error, it was extraordinarily successful. Many lead compounds were discovered by serendipity or from traditional medicine, despite a limited understanding of the pathophysiology or molecular etiology of disease. One of our oldest, yet most prototypical, drugs is acetylsalicylic acid, or Aspirin®. It is derived from bark extracts and chemically modified to improve taste and tolerability. It derives its true potency and mode of action from irreversible inhibition of cyclooxygenase. Two cyclooxygenase isoforms have been characterized, one constitutionally present and the other induced in inflamed tissue. Acetylsalicylic acid inhibits both non-selectively, resulting in some undesirable side effects. By irreversibly inhibiting COX in platelets, aspirin affects the ratio of synthesized thromboxane to prostacyclin, which has a procoagulant effect. As a result, aspirin was recommended as a “preventive medicine” to protect against thrombosis or to reduce mortality from myocardial infarction. Malaria is a widespread tropical/subtropical disease transmitted by the Anopheles mosquito. It is caused by the Plasmodium parasite, which invades human red blood cells. The disease was nearly eradicated by controlling the mosquito with the insecticide DDT. One of the oldest active ingredients against the parasite is quinine, isolated from cinchona bark. After DDT spraying for mosquitoes was discontinued, malaria returned. The parasite became increasingly resistant to known drugs, and the development of new antimalarials has been a rollercoaster ride of promising compounds and the development of resistant parasites. Morphine, isolated from the opium poppy, is used as an unaltered natural product. It is a potent analgesic. With proper administration, the risk of addiction is low. Its complex structure of five fused rings has been simplified and cut into pieces. This has resulted in more accessible analogs with greater selectivity. Cocaine is the active ingredient found in coca leaves. It is one of our oldest drugs. Its euphoric effects are achieved by displacing dopamine from its synaptic transporter. The cocaine structure served as a lead structure for the development of anesthetics. Ulcer therapy has undergone several phases of drug development, leading to active substances with increasingly efficient modes of action to reduce gastric acid production. Starting with antacids and rather non-specific anticholinergics, the development of selective H2 antagonists has been a real breakthrough in the purely pharmaceutical treatment of ulcers. They act on the H2 receptor. Proton pump inhibitors like omeprazole directly block the function of the proton-secreting H+/K+-ATPase that builds acidity. The bacterium Helicobacter pylori causes gastrointestinal damage leading to ulcers. It can be eradicated by combining a proton pump inhibitor with an antibiotic. Lifelong protection could be provided by a vaccine against the bacterium. https://sn.pub/vqibjb