Chiral Drugs: Chemistry and Biological Action

By Guo-Qiang Lin

An integrated view of chiral drugs—from concept and synthesisto pharmaceutical properties

Chirality greatly influences a drug's biological and pharmacological properties. In an effort to achieve more predictable results from chiral drugs, the Food and Drug Administration now requires that these medicines be as pure as possible, which places great demands on drug synthesis, purification, analysis, and testing. To assist researchers in acquiring the essential knowledge to meet these rigid guidelines, Chiral Drugs focuses on three vital chiral technologies—asymmetric synthesis, biocatalytic process, and chiral resolution—to offer details on the basic concepts, key developments, and recent trends in chiral drug discovery, along with:

• The history of chiral drugs development and industrial applications of chiral technologies

• A section listing twenty-five approved or advanced-trial chiral drugs that lists each drug name, chemical name and properties, a representative synthetic pathway, pharmacological characterizations, and references

• An interdisciplinary approach combining synthetic organic chemistry, medicinal chemistry, and pharmacology

Nearly two-thirds of the drugs on today's market are chiral drugs. Reducing and eliminating their negative characteristics is an ongoing and serious challenge for the pharmaceutical industry. With its well-balanced approach to covering each important aspect of chirality, Chiral Drugs champions important strategies for tipping the medical scale in a positive direction for the production of more effective—and safer—drugs.

• Language: English
• Publisher: Wiley
• Release date: Aug 8, 2011
• ISBN: 9781118075630

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Library of Congress Cataloging-in-Publication Data:

Chiral drugs : chemistry and biological action / edited by Guo-Qiang Lin, Qi-Dong You, Jie-Fei Cheng.

p. ; cm.

Includes bibliographical references and index.

ISBN 978-0-470-58720-1 (hardback)

1. Chiral drugs. 2. Drug development. 3. Structure-activity relationships (Biochemistry).

I. Lin, Guo-Qiang, 1943- II. You, Qi-Dong. III. Cheng, Jie-Fei.

[DNLM: 1. Drug Discovery-methods. 2. Pharmaceutical Preparations-chemistry.

3. Structure-Activity Relationship. QV 744]

RS429.C483 2011

615.19–dc22

2011002203

About the Editors

Professor Guo-Qiang Lin received his BS degree in chemistry from Shanghai University of Science and Technology in 1964. After completion of his graduate study at the Shanghai Institute of Organic Chemistry in 1968, he remained in the same institute and worked on natural products chemistry. He was promoted to full professorship in 1991. In 2001, he was elected as an Academician of the Chinese Academy of Sciences. His research interests include the synthesis of natural products and biologically active compounds, asymmetric catalysis, and biotransformation. He is an Executive Board Member of Editors for Tetrahedron Publications, Vice Editor-In-Chief of Acta Chimica Sinica, and Scientia Sinica Chimica. He has served as Director of the Division of Chemical Science, National Natural Science Foundation of China since 2006.

Dr. Qi-Dong You is the Dean and a Professor of the School of Pharmacy, at China Pharmaceutical University. He received his BS degree in pharmacy from the China Pharmaceutical University and completed his PhD degree in medicinal chemistry at the Shanghai Institute of Pharmaceutical Industry in 1989. He then returned to CPU as a lecturer and associate director of the Department of Medicinal Chemistry. He spent one year and a half as a senior visiting scholar in the Department of Pharmaceutical Sciences, University of Strathclyde, Glasgow, UK, before he was promoted to a full professorship in 1995. He is a council member of the China Pharmaceutical Association (CPA) and the Vice-Director of the Division of Medicinal Chemistry of CPA. His research interests include the design, synthesis, and biological evaluation of new therapeutic agents for cancer and cardiovascular and infectious diseases. He is an Associate Editor of Progress in Pharmaceutical Sciences and serves on the Editorial Board of the International Journal of Medicinal Chemistry and Acta Pharmaceutica Sinica.

Dr. Jie-Fei (Jay) Cheng was born in 1964 in Jiangxi, China. He obtained his BS degree in chemistry from the Jiangxi Normal University in 1983 and continued his graduate studies at the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, under the guidance of Professors Wei-Shan Zhou and Guo-Qiang Lin. After receiving his Master's degree in chemistry in 1986, he joined the research group of Professor Yoshimasa Hirata and Dr. Junichi Kobayashi (now a Professor at Hokkaido University) at the Mistubishi-Kasei Institute of Life Sciences, Tokyo, Japan. He then moved to Keio University to pursue his Ph.D in Professor Shosuke Yamamura's lab. Since 1993, he has been working at various pharmaceutical companies/biotechs in the United States, focusing on small-molecule drug discovery. He is currently the Director of Otsuka Shanghai Research Institute, a fully owned subsidiary of Otsuka Pharmaceutical Co. Ltd, Japan and an adjunct professor at Fudan Univeristy, China.

Contributors

CARL BEHRENS, Wilmington PharmaTech Company LLC, Newark, DE, USA, and University of Delaware, Newark, DE, USA

HAI-ZHI BU, 3D BioOptima Co. Ltd, Suzhou, Jiangsu, China

JIE-FEI (JAY) CHENG (EDITOR), Otsuka Maryland Medicinal Laboratories, Inc., Rockville, MD, USA, and, Otsuka Shanghai Research Institute, Shanghai, China

HANQING DONG, OSI Pharmaceuticals, A Wholly Owned Subsidiary of Astellas US, Farmingdale, NY, USA

XIAO-HUI GU, Otsuka Maryland Medicinal Laboratories, Inc., Rockville, MD, USA

XIAOCHUAN GUO, Drumetix Laboratories, LLC, Greensboro, NC, USA

ERIC HU, Gilead Sciences Inc., Foster City, CA, USA

HUI-YIN (HARRY) LI, Wilmington PharmaTech Company LLC, Newark, DE, USA, and University of Delaware, Newark, DE, USA

ZENGBIAO LI, Drumetix Laboratories, LLC, Greensboro, NC, USA

GUO-QIANG LIN (EDITOR), Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China

DINGGUO LIU, Pfizer, San Diego, CA, USA

YONGGE LIU, Otsuka Maryland Medicinal Laboratories, Inc., Rockville, MD, USA

RUI LIU, Wilmington PharmaTech Company LLC, Newark, DE, and University of Delaware, Newark, DE, USA

WENYA LU, Department of Chemistry, Iowa State University, Ames, Iowa, USA

CHAO-YING NI, Wilmington PharmaTech Company LLC, Newark, DE, USA, and University of Delaware, Newark, DE, USA

FENG-LING QING, Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China, and College of Chemistry and Chemistry Engineering, Donghua University, Shanghai, China

XIAO-LONG QIU, Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China

JIANGQIN SUN, Otsuka Shanghai Research Institute, Shanghai, China

XING-WEN SUN, Department of Chemistry, Fudan University, Shanghai, China

DEPING WANG, Biogen IDEC Inc., Cambridge, MA, USA

JIANQIANG WANG, ArQule Inc., Woburn, MA, USA

ZHIMIN WANG, Sundia MedTech Company Ltd., Shanghai, China

GUANG YANG, GLAXOSMITHKLINE, R&D China, Shanghai, China

QI-DONG YOU (EDITOR), China Pharmaceutical University, Nanjing, Jiangsu, China

XUYI YUE, Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China

JIAN-GE ZHANG, School of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan, China

Introduction

The book consists of 11 chapters. The first part of the book introduces the general concept of chirality and its impact on drug discovery and development. The history and the trends of chiral drug development, the technologies for the preparation of chiral drugs, and the industrial applications of chiral technologies are discussed. This part covers three important chiral technologies, namely, asymmetric synthesis, biocatalytic process, and chiral resolution, and discusses their impact on chiral drug development. Without question, fluorine atoms play an important role in chiral drug discovery and development. The significance and the preparation of fluorine-containing chiral drugs are the topic of a separate chapter.

The second part of the book mainly deals with some unique aspects of chiral drugs in terms of pharmaceutical, pharmacological, and toxicological properties. For instance, pharmacology, pharmacokinetic properties, and toxicology of chiral drugs are discussed in comparison with racemic drugs. Additionally, computational modeling as applied to chiral drug discovery and development is discussed. This part of the book provides a general knowledge of design, synthesis, screening, and pharmacology from the preclinical point of view, hoping to raise interest from a broad range of readers.

Finally, Chapter 11 covers 25 representative chiral drugs that have been approved or are in advanced clinical trials. Some natural products are not included. The most important criteria for their selection are the involvement of chiral processes during their preparation and the significance of chirality in their development. Every entry contains the trade name, chemical name and properties, a representative synthetic pathway, pharmacological characterizations, and references.

This book is intended to introduce chemists to pharmacological aspects of drug development and to form a fruitful cooperation among academic synthetic chemists, medicinal chemists, pharmaceutical scientists, and pharmacologists from the pharmaceutical and biotechnology industries. The references after each chapter will give readers an opportunity for further reading on the topics discussed. This is the first book of its kind to combine synthetic organic chemistry, medicinal chemistry, process chemistry, and pharmacology in the context of chiral drug discovery and development.

Chapter 1

Overview of Chirality and Chiral Drugs

Guo-Qiang Lin

Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China

Jian-Ge Zhang

School of Pharmaceutical Science, Zhengzhou University, Zhengzhou,China

Jie-Fei Cheng

Otsuka Shanghai Research Institute, Pudong New District, Shanghai, China

1.1 Introduction

The pharmacological activity of a drug depends mainly on its interaction with biological matrices or drug targets such as proteins, nucleic acids, and biomembranes (e.g., phospholipids and glycolipids). These biological matrices display complex three-dimensional structures that are capable of recognizing specifically a drug molecule in only one of the many possible arrangements in the three-dimensional space, thus determining the binding mode and the affinity of a drug molecule. As the drug target is made of small fragments with chirality, it is understandable that a chiral drug molecule may display biological and pharmacological activities different from its enantiomer or its racemate counterpart when interacting with a drug target. In vivo pharmacokinetic processes (ADME) may also contribute to the observed difference in in vivo pharmacological activities or toxicology profiles. One of the earliest observations on the taste differences associated with two enantiomers of asparagines was made in 1886 by Piutti (1). Colorless crystalline asparagine is the amide form of aspartic or aminosuccinic acid and is found in the cell sap of plants in two isomeric forms, levo- and dextro-asparagin. The l-form exists in asparagus, beet-root, wheat, and many seeds and is tasteless, while the d-form is sweet. Thalidomide is another classical example. It was first synthesized as a racemate in 1953 and was widely prescribed for morning sickness from 1957 to 1962 in the European countries and Canada. This led to an estimated over 10,000 babies born with defects (2). It was argued that if one of the enantiomers had been used instead of the racemate, the birth defects could have been avoided as the S isomer caused teratogenesis and induced fatal malformations or deaths in rodents while the R isomer exhibited the desired analgetic properties without side effects (3). Subsequent tests with rabbits proved that both enantiomers have desirable and undesirable activities and the chiral center is easily racemized in vivo (4). Recent identification of thalidomide's target solved the long-standing controversies (5). The chirality story about thalidomide, although not true, has indeed had great impact on modern chiral drug discovery and development (Fig. 1.1).

Figure 1.1 Asparagine (1) and thalidomide (2).

1.1

1.2 Overview of Chirality

1.2.1 Superimposability

Chirality is a fundamental property of three-dimensional objects. The word chiral is derived from the Greek word cheir, meaning hand, or handedness in a general sense. The left and right hands are mirror images of each other no matter how the two are arranged. A chiral molecule is the one that is not superimposable with its mirror image. Accordingly, an achiral compound has a superimposable mirror image. Two possible mirror image forms are called enantiomers and are exemplified by the right-handed and left-handed forms of lactic acids in Figure 1.2. Formally, a chiral molecule possesses either an asymmetric center (usually carbon) referred to as a chiral center or an asymmetric plane (planar chirality).

Figure 1.2 Mirror images of lactic acid.

1.2

In an achiral environment, enantiomers of a chiral compound exhibit identical physical and chemical properties, but they rotate the plane of polarized light in opposite directions and react at different rates with a chiral compound or with an achiral compound in a chiral environment. A chiral drug is a chiral molecule with defined pharmaceutical/pharmacological activities and utilities. The description chiral drug does not indicate specifically whether a drug is racemic, single-enantiomeric, or a mixture of stereoisomers. Instead, it simply implies that the drug contains chiral centers or has other forms of chirality, and the enantiomeric composition is not specified by this terminology.

1.2.2 Stereoisomerism

In chemistry, there are two major forms of isomerism: constitutional (structural) isomerism and stereoisomerism. Isomers are chemical species (or molecular entities) that have the same stoichiometric molecular formula but different constitutional formulas or different stereochemical formulas. In structural isomers, the atoms and functional groups are joined together in different ways. On the other hand, stereoisomers are compounds that have the same atoms connected in the same order but differ from each other in the way that the atoms are oriented in space. They include enantiomers and diastereomers, the latter indicating compounds that contain two or more chiral centers and are not superimposable with their mirror image. Diastereomers also include the nonoptical isomers such as cis-trans isomers.

Many molecules, particularly many naturally derived compounds, contain more than one chiral center. In general, a compound with n chiral centers will have 2n possible stereoisomers. Thus 2-methylamino-1-phenylpropanol with two chiral centers could have a total of four possible stereoisomers. Among these, there are two pairs of enantiomers and two pairs of diastereomers. This relationship is exemplified by ephedrines (4a, 4b) and pseudoephedrines (4c, 4d) shown in Figure 1.3. In certain cases, one of the stereoisomeric forms of a molecule containing two or more chiral centers could display a superimposable mirror image, which is referred to as a meso isomer.

Figure 1.3 Enantiomers and diastereomers.

1.3

1.2.3 Absolute Configuration

It is important to define the absolute configuration of a chiral molecule in order to understand its function in a biological system. Many biological activities are exclusive to one specific absolute configuration. Without a good understanding of absolute configuration of a molecule, it often is hard to understand its chemical and biological behavior. As mentioned above, two enantiomers of a chiral compound will have identical chemical and physical properties such as the same boiling/melting points and solubility in a normal achiral environment.

The R/S nomenclature or Cahn–Ingold–Prelog (CIP) system for defining absolute configuration is the most widely used system in the chemistry community. The key to this system is the CIP priority rule, which defines the substituent priority based on the following criteria: 1) Higher atomic number or higher atomic mass is given higher priority; 2) when the proximate atom of two or more of the substituents are the same, the atomic number of the next atom determines the priority; 3) double bonds or triple bonds are counted as if they were split into two or three single bonds, respectively; 4) cis is given higher priority than trans; 5) long pair electrons are regarded as an atom with atomic number 0; and 6) proximal groups have higher priority than distal groups.

The carbon atom in compound 5 (Fig. 1.4) is defined as a chiral center if the four substituents (X, Y, Z, and W) around the center are different. If the molecule is oriented in a way that the lowest-priority group W is pointed away from the observer and the other three groups have a priority sequence X→Y→Z in a clockwise direction, the chiral center will have a R configuration; otherwise it is defined as an S configuration. The R/S system can be used for other chiral molecules without a chiral center (e.g., planar chirality) as well (6).

Figure 1.4 A central chiral system.

1.4

Fischer's convention with D or L prefix (small cap) is sometimes used for the description of the absolute configuration of a molecule, particularly for carbohydrates or amino acids. For example, D-glyceraldehyde 6a by Fischer's convention is shown in Figure 1.5 and is identical to (R)-glyceraldehyde according to CIP rules. By relating compounds to glyceraldehydes, the absolute configuration of other compounds can be defined. For example, naturally occurring alanine 6d is designated as L-form with an S configuration.

Figure 1.5 Structure of (D)- and (L)-glyceraldehyde and analogs.

1.5

Enantiomers do differ from each other in rotating the plane-polarized light, which is referred to as optical activity or optical rotation. When an enantiomer rotates the plane of polarized light clockwise (as seen by a viewer toward whom the light is traveling), it is labeled as (+). Its mirror-image enantiomer is labeled as the (−) isomer. The (+) and (−) isomers have historically been termed d- and l-, respectively, with d for dextrorotatory and l for levorotatory rotation of the lights. This d/l system is now obsolete, and (+/–) should be used instead to specify the optical rotation. It should also be pointed out that the optical rotation (+/–) convention has no direct relation with the R/S or D/L systems. It is used in most cases for description of relative, not absolute configuration. Thus compound 3b, which rotates the plane-polarized light in a clockwise direction, is denoted as R-(+)-lactic acid, while the enantiomer (3a) is referred to S-(–)-lactic acid.

Absolute configuration is most commonly determined either by X-ray crystallography or through chemical conversion to a known compound with defined stereochemistry. Other instrumental procedures for determining absolute stereochemistry without derivatization include circular dichroism (CD), vibrational circular dichroism (VCD) (7), and optical rotator dispersion (ORD) or specific optical rotation. The NMR-based method for deducing the absolute configuration of secondary carbinol (alcohol) centers using the modified Mosher method (8) was first described by Kakisawa and co-workers (9). This modified Mosher ester analysis relies on the fact that the protons in diasteromeric α-methoxy-α-trifluoromethylphenylacetates display different arrays of chemical shifts in their ¹H NMR spectra. When correctly used and supported by appropriate data, the method can be used to determine the absolute configuration of a variety of compounds including alcohols, amines, and carboxylic acids (10). However, it is always advisable to examine the complete molecular topology in the neighborhood of the asymmetric carbon centers and confirm with another analytical method.

1.2.4 Determination of Enantiomer Composition (ee) and Diastereomeric Ratio (dr)

It is important to measure enantiomer composition and diastereomeric ratio for a chiral molecule, in particular a chiral drug, as the biological data may closely relate to the optical purity. The enantiomer composition of a sample is described by enantiomeric excess, or ee%, which describes the excess of one enantiomer over the other. Correspondingly, the diastereomer composition of a diastereomer mixture is the measure of an extent of a particular diastereomer over the others. This is calculated as shown in Equations 1 and 2, respectively, for [S] > [R] (Fig. 1.6).

Figure 1.6 Method of calculating enantiomer or diastereomer excess.

1.6

A chiral molecule containing only one enantiomeric form is regarded as optically pure or enantiopure or enantiomerically pure. Enantiomers can be separated via a process called resolution (Chapter 4), while in most cases diastereomers can be separated through chromatographic methods. A variety of methods for determination of optical purity or ee/de value are available (6). One of the widely used methods for analyzing chiral molecules is polarimetry. For any compound of which the optical rotation of the pure enantiomer is known, the ee can be determined simply from the observed rotation and calculated by Equations 3 and 4 (Fig. 1.7).

Figure 1.7 ee value is directly determined from the observed rotation.

1.7

Chromatography with chiral stationary columns, for example, chiral high-pressure liquid chromatography (HPLC) or chiral gas chromatography (GC), has also been utilized extensively for analyzing and determining enantiomeric composition of a chiral compound. Nuclear magnetic resonance (NMR) spectroscopy can also be used to evaluate the enantiomeric purity in the presence of chiral shift reagents (6, 11) or through its diastereomer derivatives (e.g., Mosher's esters) (8).

1.3 General Strategies for Synthesis of Chiral Drugs

Asymmetric synthesis refers to the selective formation of a single stereoisomer and therefore affords superior atom economy. It has become the most powerful and commonly employed method for preparation of chiral drugs. Since the 1980s, there has been progress in many new technologies, in particular, the technology related to catalytic asymmetric synthesis, that allow the preparation of pure enatiomers in quantity. The first commercialized catalytic asymmetric synthesis, the Monsanto process of L-DOPA (9) (Fig. 1.8), was established in 1974 by Knowles (12), who was awarded a Nobel Prize in Chemistry in 2001 along with Noyori and Sharpless. In the key step of the synthesis of L-DOPA, a gold standard drug for Parkinson disease, enamide compound 7 is hydrogenated in the presence of a catalytic amount of [Rh(R,R)-DiPAMP)COD]+BF4 complex, affording the protected amino acid 8 in quantitative yield and in 95% ee. A simple acid-catalyzed hydrolysis step completes the synthesis of L-DOPA (9).

Figure 1.8 Monsanto process of L-dopa (9).

1.8

The discovery of an atropisomeric chiral diphosphine, BINAP, by Noyori in 1980 (13) was revolutionary in the field of catalytic asymmetric synthesis. For example, the BINAP-Ru(II) complexes exhibit an extremely high chiral recognition ability in the hydrogenation of a variety of functionalized olefins and ketones. This transition metal catalysis is clean, simple, and economical to operate and hence is capable of conducting a reaction on a milligram to kilogram scale with a very high (up to 50%) substrate concentration in organic solvents. Both enantiomers can be synthesized with equal efficiency by choosing the appropriate enantiomers of the catalysts. It has been used in industrial production of compounds such as (R)-1,2- propanediol, (S)-naproxen, a chiral azetidinone intermediate for carbapenem synthesis, and a β-hydroxylcarboxylic acid intermediate for the first-generation synthesis of Januvia (14) among others. The Sharpless–Katsuki epoxidation was also published in 1980 (15). It has also been used for the chiral drug synthesis on an industrial scale.

Chiral compounds can now be accessed in one of many different approaches: 1) via chiral resolution of a racemate (Chapter 4); 2) through asymmetric synthesis, either chemically or enzymatically (Chapters 2 and 3); and 3) through manipulation of chiral starting materials (chiral-pool material). In the early 1990s, most chiral drugs were derived from chiral-pool materials, and only 20% of all drugs were made via purely synthetic approaches. This has now been reversed, with only about 25% of drugs made from chiral pool and over 50% from other chiral technologies (16). The following is a brief account of catalytic enantioselective synthesis with commercial applications.

1.3.1 Enantioselective Synthesis via Enzymatic Catalysis

Enzyme-catalyzed reactions (biotransformation) are often highly enantioselective and regioselective, and they can be carried out at ambient temperature, atmospheric pressure, and at or near neutral pH. Most of the enzymes used in the asymmetric synthesis can be generated in large quantity with modern molecular biology approaches. The enzyme can be degraded biochemically, therefore eliminating any potential hazardous caused by the catalysis, providing a superior and environmentally friendly method for making chiral drug molecules. It is estimated that the value of pharmaceutical intermediates generated by using enzymatic reactions was $198 million in 2006 and is expected to reach $354.4 million by 2013 (17).

(S)-6-hydroxynorleucine (11) is a key intermediate for the synthesis of omapatrilat (12), an antihypertensive drug that acts by inhibiting angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). 11 is prepared from 2-keto-6-hydroxyhexanoic acid 10 by reductive amination using beef liver glutamate dehydrogenase at 100 g/l substrate concentration. The reaction requires ammonia and NADH. NAD produced during the reaction is recycled to NADH by the oxidation of glucose to gluconic acid with glucose dehydrogenase from Bacillus megaterium. The reaction is complete in about 3 h with reaction yields of 92% and >99% ee for (S)-6-hydroxynorleucine 11 (Fig. 1.9) (18).

There are some exceptions and limitations to the enzymatic-catalyzed reactions. For example, the reaction type may be limited, and reactions may preferably be conducted in aqueous media and at low substrate concentration. However, a lot of new development in the technology of engineering enzymes have been witnessed recently (19). Enzymes can be immobilized and reused in many cycles. Selective mutations of an enzyme can alter the enzyme's performance or even make the opposite enantiomer formation possible.

Figure 1.9 Enzymatic synthesis of chiral synthon (S)-6-hydroxynorleucine (11).

1.9

1.3.2 Enantioselective Synthesis via Organometallic Catalysis

In asymmetric synthesis, a chiral agent should behave as a catalyst with enzymelike selectivity and turnover rate. Transition metal-based catalysts have been prevalent in organic synthesis for many years. Since the introduction of the Monsanto process of L-DOPA and BINAP-based ligands, asymmetric hydrogenation has become one of the most important processes in the pharmaceutical industry to synthesize key intermediates or active pharmaceutical ingredients. More than 3,000 chiral diphosphine and many monophosphine ligands have been reported, and approximately 1% of those ligands are currently commercially available (20). Besides the asymmetric hydrogenation of olefins, the ligand-mediate asymmetric hydrogenation of ketone to the corresponding alcohol (21) is becoming an indispensable alternative to other known processes such as transfer hydrogenation and biocatalytic and hydride reduction. However, a lot still remains to be improved in this field in terms of catalyst sensitivity to atmosphere, high cost, and possible toxicity.

Compounds 13–17 are examples that were generated via catalytic asymmetric hydrogenation. According to reference (22), they are sitagliptin (13), an oral diabetes drug, tipranavir (14), an HIV protease inhibitor, ramelteon (15), a sleep aid, aliskiren (16), which is a hypertension drug, and taranabant (17), the antiobesity agent (Fig. 1.10).

Figure 1.10 Example compounds generated via catalytic asymmetric hydrogenation.

1.10

1.3.3 Enantioselective Synthesis via Organocatalysis

Organocatalysts (23) have emerged as a powerful synthetic paradigm to complement organometallic- and enzyme-catalyzed asymmetric synthesis. Although examples of asymmetric organocatalysis appeared as early as the 1970s (24), the field was not born until the late 1990s and matured at the turn of the new century. Organocatalysis is now widely accepted as a new branch of enantioselective synthesis. A survey conducted by MacMillan (25) in 2008 showed only a few papers describing organocatalytic reactions before 2000, while the number of papers published in 2007 is close to 600. There have been a number of special issues of journals dedicated to asymmetric organocatalysis (26).

Organocatalysts are loosely defined as low-molecular-weight organic molecules having intrinsic catalytic activity. If an organocatalyst is modified to contain a chiral element, the reaction catalyzed by it could become enantioselective. Aside from being catalytically active, asymmetric organocatalysis are in general relatively inexpensive and readily available, are stable to atmospheric conditions, and have low toxicity. Many organocatalysts are simple derivatives of commonly available naturally occurring compounds. Representative examples include alkaloids and their derivatives (e.g., cinchonidine 18) or L-proline (19) and other natural amino acids, which function, for example, as starting materials for MacMillan-type catalysts like 20. The chiral ketone (21) generated from fructose was reported for dioxirane-mediated asymmetric epoxidation (27) (Fig. 1.11). A number of privileged organocatalysts, such as 22, 23, and 24 have been designed, synthesized, and applied to various asymmetric reactions, which include C-C, C-heteroatom bond formation, oxidation, and reduction reactions.

Figure 1.11 Representative organocatalysts.

1.11

The versatility of asymmetric organocatalysis is demonstrated by the practical synthesis of methyl (2R,3S)-3-(4-methoxyphenyl) glycidate [(–)-27], a key intermediate in the synthesis of diltiazem hydrochloride 28, which has been used as a medicine for the treatment of cardiovascular diseases since the 1970s. Methyl (E)-4-methoxycinnamate 25 underwent asymmetric epoxidation with a chiral dioxirane, generated in situ from Yang's catalyst 26, to provide the product (–)-27 in both high chemical (>85%) and optical (>70%ee) yields (Fig. 1.12) (28).

Figure 1.12 Asymmetric epoxidation of methyl (E)-4-methoxycinnamate (25).

1.12

1.4 Trends in the Development of Chiral Drugs

1.4.1 Biological and Pharmacological Activities of Chiral Drugs

Many of the components associated with living organisms are chiral, for example, DNA, enzymes, antibodies, and hormones. The enantiomers of a chiral drug may display different biological and pharmacological behaviors in chiral living systems. This can be easily understood with the example of a drug-receptor model depicted in Figure 1.13. In possession of different spatial configurations, one active isomer may bind precisely to the target sites (α, β, γ), while an inactive isomer may have an unfavorable binding or bind to other unintended targets (29). Pharmacological effects of enantiomeric drugs may be categorized as follows (30).

1.

Both enantiomers act on the same biological target(s), but one isomer has higher binding affinity than the other

For example, carvedilol (29) is marketed as a racemate for the treatment of hypertension and congestive heart failure (31). It is a nonselective β- and α-adrenergic receptor blocking agent. Nonselective β-blocking activity resides mainly in the (S)-carvedilol, and the α-blocking effect is shared by both (R)- and (S)-enantiomers (32). Sotalol (30) is a racemic β-adrenergic blocker. The (R)-enantiomer possesses the majority of the β-blocking activity, and the (R)- and (S)-enantiomers of sotalol share an equivalent degree of class III antiarrhythmic potency (33) (Fig. 1.14).

2.

Both enantiomers act on the same biological target, but exert opposed pharmacological activities

For example, (–)-dobutamine 31 demonstrated an agonistic activities against α-adrenoceptors, whereas its antipode (+)-dobutamine is an antagonist against the same receptors. The latter also acts as an β1-adrenoceptor agonist with a tenfold higher potency than the (–) isomer and is used to treat cardiogenic shock. The individual enantiomers of the 1,4-dihydropyridine analog Bayk8644 (32) have opposing effects on L-type calcium channels, with the (S)-enantiomer being an activator and the (R)-enantiomer an antagonist (34) (Fig. 1.15).

3.

Both enantiomers may act similarly, but they do not have a synergistic effect

Two enantiomers of Δ-3-tetrahydrocannabinol (S)-34 or (R)-34 were assayed in humans for psychoactivity. The 1S enantiomer 34 had definite psychic actions, qualitatively similar to those of Δ-1-tetrahydrocannabinol, but quantitatively less potent (1:3 to 1:6). Adding two enantiomers together did not increase the effect, confirming that activity was solely in one enantiomer and that there was no synergistic effect between the two isomers (35) (Fig. 1.16).

4.

Both enantiomers have independent therapeutic effects through action on different targets

The classical example of this behavior is quinine 35 and quinidine 36 (Fig. 1.17). Quinine, which was originally obtained from the bark of cinchona trees, has been used for the treatment of malaria for centuries. Quinidine, on the other hand, is used as a class 1A antiarrhythmic agent and acts by increasing action potential duration (36).

5.

One or both enantiomers have the desired effect; at the same time, only one enantiomer can cause unwanted side effects

Racemic dropropizine (37) has long been used in human therapy as an antitussive agent. Recent studies have revealed that (S)-dropropizine possesses the same antitussive activity as the racemic mixture, but has much lower selective activity on the CNS (37). Therefore, particular clinical significance is attached to drugs of which one enantiomer may contribute side or toxic effects (Fig. 1.18).

6.

The inactive enantiomer might antagonize the side effects of the active antipode

In such cases, taking into account both efficacy and safety aspects, the racemate seems to be superior to either enantiomer alone. For example, the opioid analgesic tramadol (38) is a used as a racemate and is not associated with the classical side effects of opiate drugs, such as respiratory depression, constipation, or sedation (38). The (+)-enantiomer is a selective agonist for μ receptors with preferential inhibition of serotonin reuptake and enhances serotonin efflux in the brain, whereas the (–)-enantiomer mainly inhibits noradrenaline reuptake. The incidence of side effects, particularly opioid-mediated effects, was higher with the (+)-enantiomer than with ±-tramadol or the (–)-enantiomer. Therefore, the racemate of tramadol is superior to the enantiomers for the treatment of severe postoperative pain (39). Albuterol (39), an adrenoceptor agonist bronchodilator, is the racemic form of 4-[2-(tert-butylamino)-1-hydroxyethyl]-2-(hydroxymethyl) phenol and can increase bronchial airway diameter without increasing heart rate. The bronchodilator activity resides in (R)-albuterol. (S)-albuterol, however, is not inert, as it indirectly antagonizes the benefits of (R)-albuterol and may have proinflammatory effects (40) (Fig. 1.19).

Figure 1.13 Stereoselective binding of enantiomers of a chiral drug.

1.13

Figure 1.14 Structures of carvedilol (29) and sotalol (30).

1.14

Figure 1.15 Structures of (–)-dobutamine (31) and Bayk8644 (32).

1.15

Figure 1.16 Structures of dextromethorphan and Δ-3-tetrahydrocannabinol (S)-34 or (R)-34.

1.16

Figure 1.17 Structures of quinine (35) and quinidine (36).

1.17

Figure 1.18 Structures of dropropizine (37).

1.18

Figure 1.19 Structures of tramadol (38) and albuterol (39).

1.19

It is a difficult task to rationally predict the biological/pharmacological activity difference for two enantiomers. Fokkens and Klebe developed a simple protocol using isothermal titration calorimetry in an attempt to semiquantitatively determine the difference in binding affinity of two enantiomers to a protein without requiring prior resolution of the racemates (41). In some cases, the affinity difference could be explained in terms of differences in the structural fit of the enantiomers into the binding pocket of the protein. (42).

Many attempts were made to develop a quantitative structure-activity relationship between the two enantiomers and a specific target or target families. The ratio of potency or affinity of two enantiomers is defined as the eudismic ratio (ER). The more potent enantiomer is generally called the eutomer, and the less potent enantiometer is the distomer. The logarithm of the eudimic ratio is regarded as the eudismic index (EI). Pfeiffer made an initial observation that the logarithm of the ratio of the activities of the optical isomers was proportional to the logarithm of the human dose. The generalization that the lower the effective dose of a drug, the greater the difference in pharmacological effect between the optical isomers is referred as Pfeiffer's rule (43). Indeed, a linear correlation between the logarithm of the EI of 14 randomly chosen enantiomeric pairs and the logarithm of the average human dose was observed.

Eudismic analysis was made for a series of five cholinesterase inhibitors, derivatives of S-alkyl p-nitrophenyl methylphosphonothiolates (R: methyl to pentyl), a series of four derivatives of 1,3-dioxolane (R: H, Me, Et, i-propyl) active at the muscarinic receptor, and Pfeiffer's original set of 14 nonhomologous enantiomeric pairs with a computer-aided drug design method [44]. It was concluded that eudismic ratios of potent drugs belonging to homologous sets can be correlated with their chirality coefficients, which was defined as the quantitative index of the dissimilarity between the enantiomers and was calculated from a combination of data from the superimposition of computer-optimized conformations and electrostatic potential (ESP) calculations. Linear correlations were observed between the calculated chirality coefficients and experimentally determined eudismic ratios for both sets of homologous derivatives. With Pfeiffer's set (members include atropine, norepinephrine, epinephrine, and methadone) correlation was observed for the first (most potent) eight members of the series. The lack of correlation for the less potent compounds in Pfeiffer's set was explained as a function of kinetic differences becoming more influential than drug-receptor interactions (44).

On the qualitative side, 3D binding molecule modeling studies can point out some interesting binding differences for two enantiomers. Two enantiomers of citalopram were demonstrated to bind to human serotonin transporter in reversed orientation (45).

1.4.2 Pharmacokinetics and Drug Disposition

In addition to the differences in biological activities, stereoisomers may differ in their pharmacokinetic properties such as absorption, distribution, metabolism, and excretion (ADME) as a result of chiral discrimination during the pharmacokinetic processes (46). The difference in bioavailability, rate of metabolism, metabolite formation, excretion rate, and toxicity may be further influenced by other factors such as the route of administration, the age and sex of the subjects, disease states, and genetic polymorphism in cytochrome P450 (CYP) isoenzymes involved in drug metabolism (47).

Active transport processes may discriminate between the enantiomers, with implications for bioavailability. For example, a longer plasma half-life in the rabbit and greater accumulation of propranolol in the heart and brain of the rat were found for the active (S)-(–)-enantiomer (40) as compared to the corresponding racemate.

Plasma binding capacity for two enantiomers may also be significantly different, thus influencing drug efficacy. Methadone (41), introduced to treat opioid dependence in 1965, has therapeutic benefits that reside in the (R)-enantiomer. Compared to the (S)-enantiomer of methadone, methadone's (R)-enantiomer shows 10-fold higher affinity for μ and κ opioid receptors and up to 50 times the antinociceptive activity in animal model and clinical studies. Methadone's enantiomers show markedly different pharmacokinetics. The (R)-enantiomer shows a significantly greater unbound fraction and total renal clearance than the (S)-enantiomer. This reflects higher plasma protein binding of the (S)-enantiomer (48) (Fig. 1.20).

Figure 1.20 Structures of (S)-(–)-propranolol (40) and methadone (41).

1.20

Similarly, enzymes that metabolize drug molecules may also discriminate enantiomers differently. For example, esomeprazole 42 (S-isomer of omeprazole), an optical isomer proton pump inhibitor, generally provides better acid control than the current racemic proton pump inhibitors and has a favorable pharmacokinetic profile relative to omeprazole. However, the metabolic profiles of the two drugs are different, leading to different systemic exposures and thus different pharmacodynamic effects. Metabolism of the (R)-enantiomer is more dependent on CYP2C19, whereas the (S)-enantiomer can be metabolized by alternative pathways like CYP3A4 and sulfotransferases (Fig. 1.21). This results in the less active (R)-enantiomer achieving higher concentrations in poor metabolizers, which may in the long term cause adverse effects like gastric carcinoids and hyperplasia (29, 49).

Figure 1.21 Main metabolites of (S)-omeprazole (42).

1.21

The more advantageous pharmacokinetics for both enantiomers is found in the metabolic distribution, clearance, and so on. Cetirizine (Zyrtec), the potent histamine H1 receptor antagonist, is a racemic mixture of (R)- and (S)-dextrocetirizine 43 (Fig. 1.22). In binding assays, levocetirizine has demonstrated a twofold higher affinity for the human H1 receptor compared to cetirizine, and an approximately 30-fold higher affinity than dextrocetirizin (50). However, levocetirizine is rapidly and extensively absorbed and poorly metabolized and exhibits comparable pharmacokinetic profiles with the racemate. Its apparent volume of distribution is smaller than that of dextrocetirizine (0.41 l/kg vs. 0.60 l/kg). Moreover, the nonrenal (mostly hepatic) clearance of levocetirizine is also significantly lower than that of dextrocetirizine (11.8 ml/min vs. 29.2 ml/min). All evidence available indicates that levocetirizine is intrinsically more active and more efficacious than dextrocetirizine, and for a longer duration (51).

Figure 1.22 Structures of (R)-levocetirizine and (S)-dextrocetirizine.

1.22

Although it is well known that cytochrome P450 enzyme can accommodate a wide range of substrates, it is still possible for two isomers of a drug to induce or inhibit these enzymes differently, either with different modes of action or with different enzyme subtypes. Trimipramine (44) is a tricyclic antidepressant with sedative and anxiolytic properties. Desmethyl-trimipramine (45), 2-hydroxy-trimipramine (46) and 2-hydroxy-desmethyl-trimipramine (47) are the main metabolites of trimipramine (Fig. 1.23). However, trimipramine appears to show stereoselective metabolism with preferential N-demethylation of D-trimipramine and preferential hydroxylation of L-trimipramine, mediated by CYP2D6. CYP2C19 appears to be involved in demethylation and favors the D-enantiomer, while CYP3A4 and CYP3A5 seem to metabolize L-trimipramine to a currently undetermined metabolite (52).

Figure 1.23 Metabolism