Most new drugs or drug products are discovered or developed through the following approaches:
(1) identification or elucida-tion of a new drug target;
(2) rational design of a new molecule based on an understanding of biologic mechanisms and drug receptor structure;
(3) screening for biologic activity of large numbers of natural products, banks of previously discovered chemical entities, or large libraries of peptides, nucleic acids, and other organic molecules; and
(4) chemical modification of a known active molecule, resulting in a me-too analog. Steps (1) and (2) are often carried out in academic research laboratories, but the costs of steps (3) and (4) usually ensure that industry carries them out.
Once a new drug target or promising molecule has been identi-fied, the process of moving from the basic science laboratory to the clinic begins. This translational research involves the pre-clinical and clinical steps described next.
Drug Screening
Regardless of the source or the key idea leading to a drug candi-date molecule, testing it involves a sequence of experimentation and characterization called drug screening. A variety of assays at the molecular, cellular, organ system, and whole animal levels are used to define the activity and selectivity of the drug. The type and number of initial screening tests depend on the pharmacologic and therapeutic goal. For example, anti-infective drugs may be tested against a variety of infectious organisms, some of which areresistant to standard agents; hypoglycemic drugs may be tested for their ability to lower blood sugar, etc.
The molecule will also be studied for a broad array of other actions to determine the mechanism of action and selectivity of the drug. This can reveal both expected and unexpected toxic effects. Occasionally, an unexpected therapeutic action is seren-dipitously discovered by a careful observer. The selection of com-pounds for development is most efficiently conducted in animal models of human disease. Where good predictive preclinical mod-els exist (eg, antibacterials, hypertension, or thrombotic disease), we generally have good or excellent drugs. Good drugs or break-through improvements are conspicuously lacking and slow for diseases for which preclinical models are poor or not yet available, eg, autism and Alzheimer’s disease.Studies are performed during drug screening to define the pharmacologic profile of the drug at the molecular, cellular,organ, system, and organism levels. The value of these tests is highly dependent on the reproducibility and reliability of the assays. For example, a broad range of tests would be performed on a drug designed to act as an antagonist for a new vascular target for the treatment of hypertension.At the molecular level, the compound would be screened for activity on the target, for example, receptor binding affinity to cell membranes containing the homologous animal receptors (or if possible, on the cloned human receptors). Early studies would be done to predict effects that might later cause undesired drug metabolism or toxicologic complications. For example, studies on liver cytochrome P450 enzymes would be performed to determine whether the molecule of interest is likely to be a substrate or inhibitor of these enzymes or to interfere with the metabolism of other drugs.
Effects on cardiac ion channels such as the hERG potassium channel, possibly predictive of life-threatening arrhyth-mias, are considered.Effects on cell function determine whether the drug is an ago-nist, partial agonist, inverse agonist, or antagonist at the relevant receptors. Isolated tissues, especially vascular smooth muscle, would be used to characterize the pharmacologic activity and selectivity of the new compound in comparison with reference compounds. Comparison with other drugs would also be under-taken in other in vitro preparations such as gastrointestinal and bronchial smooth muscle.
