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Vol. 32 No. 4
July-August 2010

Analogue-based Drug Discovery

by János Fischer and C. Robin Ganellin

Analogy plays a very important role in scientific research, and especially in applied research. This is certainly true for the medicinal chemist searching for new drugs to treat diseases. The chemical structure and the similarities and differences in chemical and biological properties between compounds helps to guide the researcher in deciding where to position a new molecule in comparison to what is already known about other compounds.

The book Analogue-based Drug Discovery, published by Wiley-VCH in 2006, provided the first authoritative overview of past and current strategies for successful drug development by molecular modification of known leads was. This unique resource spanned the important drug classes in most major therapeutic fields. A second edition* was released this month that has a broader scope than the first and which not only contains descriptions of full analogues, but also includes several pharmacological analogues.

(* Analogue-based Drug Discovery II Janos Fischer and C. Robin Ganellin (editors) July 2010. 600 Pages, Hardcover, Handbook/Reference Book ISBN-10: 3-527-32549-2 ISBN-13: 978-3-527-32549-8 Wiley-VCH, Weinheim; view content and sample chapter on wiley-vch.ed).

Medicinal chemistry is a relatively “young” science which has spanned the whole of the 20th century. In the first half of the century, new drug research was dominated by organic chemistry, and researchers sought improved drugs among structurally similar compounds. Full analogues dominated this kind of research. The latter half of the century saw a much greater contribution from biochemistry and pharmacology and many pioneer drugs were discovered. This opened the way for researchers to seek to improve upon these drugs by investigating analogues.

The first edition of Analogue-based Drug Discovery was focused on an important segment of medicinal chemistry, where an existing drug was selected as a lead compound and the research had, as a goal, to improve upon the lead by synthesizing and testing analogues. The chemical structure and main biological activity of such an analogue were often similar to the lead drug. Thus, the researchers generally sought a structural and pharmacological analogue, (more simply called a full analogue) or, if the pharmacophores were the same, a direct analogue. Usually the aim was to achieve an improved biological activity profile, with a greater potency.

The first edition included a description of many well-established analogue classes of drug that are indispensable nowadays for the treatment of peptic ulcer disease, gastroesophageal reflux disease, prevention of cardiovascular diseases (e.g,. antihypertensives, cholesterol-lowering agents, calcium antagonists, beta-adrenergic receptor blocking agents), pain (e.g., opioid analgesics), and many other diseases.

The last two decades, however, have witnessed great changes in the chemical and biological methods for generating a lead compound. Combinatorial chemistry affords many more compounds than traditional synthetic methods and these are tested very rapidly by high throughput screening (HTS) to deliver new hit and lead molecules. This procedure often opens the way to new types of structures for drug research, thereby decreasing the importance of having chemical similarity. At the same time, this improves the opportunity for novelty and therefore for patenting. This also gives rise to a greater need to compare the biological properties of these new lead compounds in order to arrive at the best pharmacological analogue.

Analogue-based Drug Discovery is not a simple research method, but it is a way of thinking that, in addition to organic synthesis, uses most of the procedures that are now available to medicinal chemists, such as the following:

  • investigation of structure-activity relationships
  • molecular modeling
  • structure-based drug discovery
  • fragment-based drug discovery
  • early recognition of drug distribution properties and avoidance of potential toxicities

Analogue-based Drug Discovery has the merit that the therapeutic target is already validated, but it carries the hazard of potentially losing out to competitors who may start from the same approach at about the same time.

The new 2010 edition is comprised of three parts:

  • General Aspects of Analogue-based Drug Discovery
  • Analogue Classes
  • Case Histories

The opening chapter summarizes various ways to modify the properties of a drug to make a new drug analogue that improves patient drug therapy. There are 12 principles exemplified (see box below), and within some of these principles there are several methods; hence, the chapter provides a broad overview.

A small number of the pioneer drugs remain without having successful analogues; we describe these by the term standalone drug. Among the most frequently used 100 drugs, nine such standalone drugs can be identified (see box below). Their history and present situation may be used to initiate new research activity to make analogues of them.

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.

In addition to the traditional structure-activity relationship studies, molecular modeling is the most important method that the medicinal chemist can use to find a new drug analogue. The chapter discusses several useful examples of molecular modeling in analogue research.

Patenting activity is one of the basic tasks of drug research. Patents mostly concern a group of direct analogues; therefore, the first claim of a patent contains a general structure which describes this group of compounds. The chapter gives an overview of some of the issues that can affect the commercial protection of the discoveries made by medicinal chemists.

Analogue Classes
The second chapter on Analogue Classes describes the following nine categories of analogues.

The discovery of dipeptidyl peptidase IV inhibitors opens a promising chapter for the treatment of type 2 diabetes. The pioneer drug sitagliptin has been followed by several analogues in order to obtain more potent and longer-acting derivatives.

Serendipitious clinical observation afforded the pioneer drug sildenafil. Several analogues have been found that have optimized its properties (e.g., selectivity, duration of action).

Rifamycins are antibacterial antibiotics derived from fermentation. Analogue-based drug research afforded more potent derivatives. One of the derivatives, the poorly absorbed rifaximin, has a promising application for the treatment of irritable bowel syndrome.

Three analogue classes of monoterpenoid indole alkaloids are discussed: i) vincamine derivatives, ii) dimeric vinca alkaloid analogues, and iii) camptothecin analogues. The succesful natural product direct analogues are applied to the treatment of cerebral insufficiencies and cancer.

The natural product doxorubicin is an anthracycline antibiotic used to treat a wide range of cancers but it has a cardiotoxic adverse effect. The research into direct analogues had a goal to obtain drugs with a better therapeutic index.

Paclitaxel and epothilone analogues are also examples of how natural product drugs can be used to initiate analogue-based drug research to afford new drug analogues with better properties as anticancer agents.

The selective serotonin reuptake inhibitors (SSRIs) are pharmacological analogues that revolutionized antidepressant therapy. The structurally different SSRIs have different profiles for inhibiting uptake of the neurotransmitters serotonin, dopamine, and norepinephrine.

The modification of naturally occurring tropane alkaloids afforded the quaternary ammonium salts ipratropium and tiotropium, which are important drugs used for treating chronic obstructive pulmonary disease. Tiotropium—as a result of analogue-based drug discovery—has a longer duration of action that enables a once daily dosing.

The natural product adrenaline (epinephrine) was the starting point for drug research into β-adrenoreceptor agonists. From isoprenaline (isoproterenol) through the selectively acting salbutamol, and on to salmeterol, analogue research resulted in selective, more potent, and longer-acting analogues with different PK profiles, which are important drugs in asthma therapy.

Case Histories
In the final section of the book, eight case histories are described by their inventors.

Liraglutide is a new antidiabetic drug, an analogue of the natural product glucagon-like peptide 1. Among the acylated GLP-1 analogues liraglutide has been developed for a once-daily treatment.

Eplerenone is a spironolactone analogue for treating hypertension that has a greater selectivity for the mineralocorticoid receptor and reduced sexual side-effects.

Clevudine is a new drug for the treatment of the chronic hepatitis B virus (HBV) infection, which belongs to the class of nucleoside reverse transcriptase inhibitors.

Tipranavir is a new anti-HIV agent that is a protease inhibitor. The discovery of tipranavir used structure-based and fragment-based drug design and its long discovery process started from warfarin, which is a weak HIV-1 protease inhibitor.

Dasatinib can be regarded as a pharmacological analogue of imatinib. Dasatinib is more potent and it can be used in imatinib-resistant cases for the treatment of chronic myologenous leukemia (CML).

Lapatinib can be regarded as a pharmacological analogue of erlotinib. It is a tyrosine kinase inhibitor and was first approved for the treatment of solid tumors such as in breast cancer.

Venlafaxine is the first marketed serotonin/norepinephrine reuptake inhibitor and is used for the treatment of deep depression. Its active metabolite is desvenlafaxine, which has some advantageous properties (e.g., it has a more favorable metabolic profile compared to venlafaxine).

Rilpivirine is a new HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI), an analogue of etravirine. Rilpivirine is highly potent also against strains that are resistant to the first-generation NNRTI drugs.

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.

János Fischer <[email protected]> Ph.D., works at Richter Plc. in Budapest, Hungary. C. Robin Ganellin <[email protected]> is a professor at University College London, in London, UK. Both have been members of the Chemistry and Human Health Division of IUPAC for several years and have collaborated on several projects involving international teams of experts.

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