Analogue-based Drug Discovery III

János Fischer, C. Robin Ganellin, David P. Rotella, János Fischer, C. Robin Ganellin, David P. Rotella

• Publisher: Wiley-VCH
• Year: 2012
• Print ISBN: 9783527330737
• eBook ISBN: 9783527651108
• Edition: 1
• Topic: Medicine
• Subtopic: Pharmacology

Most drugs are analogue drugs. There are no general rules how a new drug can be discovered, nevertheless, there are some observations which help to find a new drug, and also an individual story of a drug discovery can initiate and help new discoveries. Volume III is a continuation of the successful book series with new examples of established and recently introduced drugs.
The major part of the book is written by key inventors either as a case study or a study of an analogue class. With its wide range across a variety of therapeutic fields and chemical classes, this is of interest to virtually every researcher in drug discovery and pharmaceutical chemistry, and -- together with the previous volumes -- constitutes the first systematic approach to drug analogue development.

Part I

General Aspects

1

Pioneer and Analogue Drugs

János Fischer, C. Robin Ganellin, and David P. Rotella

A pioneer drug (“first in class”) represents a breakthrough invention that affords a marketed drug where no structurally and/or pharmacologically similar drug was known before its introduction. The majority of drugs, however, are analogue drugs, which have structural and/or pharmacological similarities to a pioneer drug or, as in some cases, to other analogue drugs.

The aim of this chapter is to discuss these two drug types [1].

The term “pioneer drug” is not used very often, because only a small fraction of drugs belongs to this type and in many cases the pioneer drugs lose their importance when similar but better drugs are discovered. A pioneer drug and its analogues form a drug class in which subsequent optimization may be observed. Analogue drugs typically offer benefits such as improved efficacy and/or side effect profiles or dose frequency than a pioneer drug to be successful on the market.

The discovery of both pioneer and analogue drugs needs some serendipity. A pioneer drug must clinically validate the safety and efficacy of a new molecular target and mechanism of action based on a novel chemical structure. In the case of an analogue drug, it is helpful that a pioneer or an analogue exists; nevertheless, some serendipity is needed to discover a new and better drug analogue, because there are no general guidelines on how such molecules can be identified preclinically. The analogue approach is very fruitful in new drug research, because there is a higher probability of finding a better drug than to discover a pioneer one. A significant risk with this approach is based on the potential for one of the many competitors in the drug discovery area to succeed prior to others.

The similarity between two drugs cannot be simply defined. Even a minor modification of a drug structure can completely modify the properties of a molecule. Levodopa (1) and methyldopa (2) are applied in different therapeutic fields; however, their structures differ only in a methyl group. Both molecules have the same stereochemistry as derivatives of l-tyrosine. Levodopa [2] is used for the treatment of Parkinson's disease as a dopamine precursor, whereas methyldopa [3] was an important antihypertensive agent before safer and more efficacious molecules (e.g., ACE inhibitors) appeared on the market.

Methyldopa (first synthesized at Merck Sharp & Dohme) has a dual mechanism of action: it is a competitive inhibitor of the enzyme DOPA decarboxylase and its metabolite acts as an α-adrenergic agonist.

Levodopa and methyldopa are not analogues from the viewpoint of medicinal chemistry. Both are pioneer drugs in their respective therapeutic fields and can be considered as stand-alone drugs, because they have no successful analogues.

There are several examples, and it is a usual case that a minor modification of a drug molecule affords a much more active drug in the same therapeutic field. The pioneer drug chlorothiazide (3) and its analogue hydrochlorothiazide (4) from Merck Sharp & Dohme differ only by two hydrogen atoms; however, the diuretic effect of hydrochlorothiazide [4] is 10 times higher than that of the original drug. The pioneer drug chlorothiazide is rarely used, but its analogue, hydrochlorothiazide, is an important first-line component in current antihypertensive therapy as a single agent and in combination with other compounds.

Chlorothiazide and hydrochlorothiazide are direct analogues, which term emphasizes their close relationship.

The terms “pioneer drugs” and “analogue drugs” will be discussed in the following sections.

1.1 Monotarget Drugs

1.1.1 H₂ Receptor Histamine Antagonists

Before the launch of cimetidine (1976), only short-acting neutralization of gastric acid was possible by administration of various antacids (e.g., sodium bicarbonate, magnesium hydroxide, aluminum hydroxide, etc.) that did not affect gastric acid secretion. Cimetidine [5], the first successful H₂ receptor histamine antagonist, a pioneer drug for the treatment of gastric hyperacidity and peptic ulcer disease, was discovered by researchers at Smith, Kline & French. The inhibition of histamine-stimulated gastric acid secretion was first studied in rats. Burimamide (5) was the first lead compound, a prototype drug, that also served as a proof of concept for inhibition of acid secretion in human subjects when administered intravenously, but its oral activity was insufficient. Its analogue, metiamide (6), was orally active, but its clinical studies had to be discontinued because of a low incidence of granulocytopenia. Replacing the thiourea moiety in metiamide with a cyanoguanidino moiety afforded cimetidine (7). Its use provided clinical proof for inhibition of gastric acid secretion and ulcer healing and was a great commercial and clinical success in the treatment of peptic ulcer disease.

Although cimetidine was very effective for the treatment of peptic ulcer disease and related problems of acid hypersecretion, there were some side effects associated with its use, albeit at a very low level. A low incidence of gynecomastia in men can occur at high doses of cimetidine due to its antiandrogen effect. Cimetidine also inhibits cytochrome P450, an important drug metabolizing enzyme. It is therefore advisable to avoid coadministration of cimetidine with certain drugs such as propranolol, warfarin, diazepam, and theophylline.

Cimetidine led to the initiation of analogue-based drug research affording more potent analogue drugs such as ranitidine (8) and famotidine (9) that lack the above side effects of cimetidine.

Ranitidine [6] also has a pioneer character, because ranitidine is the first H₂ receptor histamine antagonist that has no antiandrogen adverse effect and does not inhibit the cytochrome CYP450 enzymes. Famotidine is the most potent member of this drug class, which has been discussed in Volume I of this series [7].

Summary:

Pioneer H₂ receptor histamine antagonist: cimetidine.

First H₂ receptor histamine antagonist with no antiandrogen adverse effects and without inhibition of P450 enzymes: ranitidine.

1.1.2 ACE Inhibitors

A natural product, the nonapeptide teprotide (10), was the pioneer drug for angiotensin-converting enzyme (ACE) inhibitors. Teprotide [8] was used as an active antihypertensive drug in patients with essential hypertension. It could only be administered parenterally, which is a great drawback for chronic use of a drug. A breakthrough occurred with the approval of the first orally active ACE inhibitor captopril (11) in 1980 by Squibb. Captopril [9] has a short onset time (0.5–1 h), and its duration of action is also relatively short (6–12 h); as a result, two to three daily doses are necessary. Captopril can be regarded as a pharmacological analogue of teprotide, but it is also the pioneer orally active ACE inhibitor. Captopril's discovery initiated intensive research by several other drug companies to discover longer acting ACE inhibitors. Enalapril (12) was introduced by Merck in 1984. Enalapril [10] can be regarded as the first long-acting oral ACE inhibitor. The long-acting ACE inhibitors are once-daily antihypertensive drugs. There are several long-acting ACE inhibitors, whose differences have been discussed in the first volume of this book series [11].

Summary:

Pioneer ACE inhibitor drug: teprotide.

First orally active ACE inhibitor drug: captopril.

First orally long-acting ACE inhibitor drug: enalapril.

1.1.3 DPP IV Inhibitors

Sitagliptin (13) [12], a pioneer dipeptidyl peptidase IV (DPP IV) inhibitor, was launched in 2006 by Merck for the treatment of type 2 diabetes. The medicinal chemistry team began its research in 1999 when some DPP IV inhibitor molecules were known as substrate-based analogues. The lead molecule derived from this research was vildagliptin (14) [13]; discovered at Novartis in 1998, it was the second compound to be introduced to the market.

The pioneer drug sitagliptin is a commercial success with 2010 sales greater than USD 3 billion. Vildagliptin was the first successful discovery in this drug class, but its development time was longer and it was introduced in 2007, after sitagliptin. Vildagliptin is only moderately selective over DPP-8 and DPP-9 compared to sitagliptin that is a highly selective DPP IV inhibitor. Based on long-term safety studies, these selectivity differences do not influence the toxicity of vildagliptin. Sitagliptin and vildagliptin show similar clinical efficacies. Vildagliptin has a short half-life (3 h) and its dosing regimen is twice a day, whereas sitagliptin has a long half-life (12 h) and once-daily dosing is used. DPP IV inhibitors are typical early-phase analogues that result from a highly competitive industry, and not the first candidate (vildagliptin) but a follow-on drug (sitaglip...

Table of contents

• Cover
• Related Titles
• Title Page
• Copyright
• Preface
• List of Contributors
• Part I: General Aspects
• Part II: Drug Classes
• Part III: Case Studies
• Index