Twelve Principles for Drug Optimization
|1. Increasing Potency
In the analogue class of the histamine H2-receptor antagonists (cimetidine, nizatidine, ranitidine, roxatidine, and famotidine), an increasing potency of the drug analogues can be observed. Famotidine is the most potent member of this class.2. Improving the Ratio of the Main Activity to Adverse Affects
The pioneer drug of the adrenergic β-blockers is propranolol, which blocked both β1– and β2-receptors. However, blocking β2-receptors in asthma is harmful. Several selective blockers were developed and used in cardiology, such as atenolol, metoprolol, etc.
3. Improving the Physicochemical Properties with the Help of Analogues
4. Decreasing Resistance to Anti-Infective Drugs
5 .Decreasing Resistance to Anticancer Agents
6. Improving Oral Bioavailability
|based drug research afforded the lysylproline analogue, lisinopril, which has an acceptable bioavailability and it does not require metabolic activation.
7. Long-Acting Drugs for Chronic Diseases
8. Ultrashort-Acting Drugs in Emergency Cases
9. Decreasing Interindividual Pharmacokinetic Differences
10. Decreasing Systemic Activities
11. Decreasing Drug Interactions with the Help of Analogues
12. Synergistic Interactions between Analogues
Points for Drug Optimizations
We analyzed the Top 100 most frequently used drugs and nine standalone drugs were identified, that is, pioneer drugs for which there are no effective analogues. These are the following drugs: acetaminophen, acetylsalicylic acid, aripiprazole, bupropion, ezetimibe, lamotrigine, metformin, topiramate, and valproate semisodium.
Acetaminophen is one of the oldest drugs, which even nowadays has a broad application as an analgesic and antipyretic agent. However, acute overdose can cause severe hepatic damage.
Acetylsalicylic acid (aspirin) is also one of the oldest drugs and, contrary to acetaminophen, its mechanism of action is partly known: it irreversibly inhibits the cyclooxygenase-1 enzyme. A more potent derivative with a better adverse effect profile would be advantageous.
Aripiprazole is a relatively new antipsychotic drug which acts as a dopamine partial agonist for the treatment of schizophrenia. A more effective drug is needed for the treatment of refractory patients, to improve treatment of negative symptoms and cognitive dysfunction.
Bupropion is a unique antidepressant drug. It is the first non-nicotine medication for the treatment of smoking cessation.
Ezetimibe is a relatively new cholesterol absorption inhibitor. Its mechanism of action was discovered only recently (2005). Analogue-based drug research is underway.
Lamotrigine, topiramate, and valproate are widely used anticonvulsant drugs, whose mechanism of action is not known. Several efforts have been made to find better analogues, so far without positive results.
Metformin is already an old standalone drug for the treatment of type 2 diabetes. It is used alone or in combination with new antidiabetic agents. Its mechanism of action is not known which makes it difficult to conduct an analogue-based drug research.