Twelve Principles for Drug Optimization

 DRUG DESIGN, drugs  Comments Off on Twelve Principles for Drug Optimization
Jan 092016


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
Benzylpenicillin (penicillin G) was a pioneer antibiotic molecule, which could be administered only by intramuscular injection because of its acid-sensitivity. Through analogues, stable molecules were obtained and they could be given orally (e.g., ampicillin).

4. Decreasing Resistance to Anti-Infective Drugs
Resistance to anti-infective drugs has become an increasing problem all over the world. The widespread use of penicillin G led to an alarming increase of penicillin-G resistant Staphylococcus aureus infections in 1960. A solution to the problem was the design of penicillinase-resistant penicillins. Several examples show that analogues can also overcome the resistance to antifungal and antiviral drugs.

5 .Decreasing Resistance to Anticancer Agents
Imatinib is the pioneer drug for the treatment of chronic myelogenous leukemia. However, a significant number of patients develop resistance to imatinib. New analogues, such as dasatinib and nilotinib, have been introduced recently and it is hoped that these analogues will be effective in imatinib-resistant cases.

6. Improving Oral Bioavailability
A good oral bioavailability is necessary in most cases because the oral application of a drug is preferred to an injection therapy. Enalaprilat is an angiotensin-converting enzyme inhibitor which is used in intravenous administration for the treatment of hypertensive emergencies. Its ester prodrug has an excellent oral bioavailability, but it requires hydrolysis by esterases. Analogue-

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
Quaternary antimuscarinics are important drugs for the treatment of chronic obstructive pulmonary disease. Ipratropium bromide is a very active bronchodilator that is used several times daily. Its analogue is tiotropium with a longer duration of action which enables a once-daily dosing.

8. Ultrashort-Acting Drugs in Emergency Cases
Esmolol is an adrenergic β1-selective blocker with a very short duration of action. It is used when β-blockade of very short duration is desired in emergency situations.

9. Decreasing Interindividual Pharmacokinetic Differences
Omeprazole is a pioneer proton pump inhibitor that shows interindividual variability. Analogue-based drug discovery afforded pantoprazole with a linear, highly predictable pharmacokinetic property.

10. Decreasing Systemic Activities
For intranasal and inhalation applications of corticosteroids in the treatment of asthma and rhinitis, it is important to decrease the systemic availability of these drugs to avoid their adverse effects. Analogue research afforded budenoside and fluticasone with a low oral bioavailability.

11. Decreasing Drug Interactions with the Help of Analogues
Cimetidine inhibits CYPs, an important class of drug-metabolizing enzymes. This interaction inhibits the metabolism of certain drugs, such as propranolol, warfarin, diazepam, thus producing effects equivalent to an overdose of these medicines. These effects are avoided by analogues such as ranitidine and famotidine.

12. Synergistic Interactions between Analogues
Analogue-based drug research starting from ritonavir, which is an HIV-1 protease inhibitor, afforded the more potent lopinavir. However, it has a low plasma half- life. A combination of ritonavir and lopinavir is very successful, because ritonavir inhibits the P-450-mediated metabiolism of lopinavir.


Standalone Drugs Can Be Starting
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.




Piece by Piece A guide to fragment-based drug discovery

 DRUG DESIGN, drugs  Comments Off on Piece by Piece A guide to fragment-based drug discovery
Dec 222014

DESIGNING A BETTER DRUG: The combination of chemical groups from three different fragments that bind weakly to an enzyme produce a potent new enzyme inhibitor (center) that binds in the nM range.COURTESY OF RODERICK HUBBARD

In search of better drugs and therapies, researchers are constantly looking for new ways to identify compounds that selectively block disease pathways. Industrial labs have relied on high-throughput screening to finger promising new molecules, but most academic labs lack the equipment and resources to scan many thousands, even millions, of compounds. For a long while this shut academic labs out of such searches, but a related technique, fragment-based drug discovery (also called fragment-based lead discovery), offers another way to develop small-molecule drugs and chemical probes for investigating biological processes. And this approach relies on instruments and expertise available at many academic institutions.

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Piece by Piece

A guide to fragment-based drug discovery



More and more companies are using fragment-based lead design as a drug discovery strategy

 DRUG DESIGN  Comments Off on More and more companies are using fragment-based lead design as a drug discovery strategy
Apr 222014

shaking hands
Small fragments that bind in nearby pockets can be connected to make a lead.

In the pursuit of new pharmaceuticals, many medicinal chemists want to start their leg of the drug discovery race with a drug-sized molecule that binds with a tenacious grip—we’re talking nanomolar potency—to its biological target. After all, there are so many molecular traits to optimize, such as reducing a drug lead’s toxicity and increasing its solubility in the body, that beginning with high-binding affinity seems like starting on the right foot. That’s why high-affinity hits are the primary aim of high-throughput screening (HTS), a bread-and-butter starting point for drug lead discovery.

But a growing number of medicinal chemists are leaving the high-affinity paradigm behind. These researchers are sidestepping some of the cherished tenets of HTS in favor of an emerging drug discovery strategy called fragment-based lead discovery (FBLD).



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