PJP5'2004.Vp:Corelventura

Home , Barnidipine, Cromakalim

“…I’ll tell you all my ideas about Looking Glass House. First, there’s the room you can see through the glass – that’s just the same as our drawing room, only the thing go other way… Well then, the books are something like our books, only the words go the wrong way; …I wonder if they’d give you milk in there? Perhaps Looking-Glass milk isn’t good to drink…”

“Through the Looking Glass” Lewis Caroll (1832–1898)

REVIEW

INFLUENCE OF THE ABSOLUTE CONFIGURATION ON PHARMACOLOGICAL ACTIVITY OF ANTIHYPERTENSIVE AND ANTIARRHYTHMIC DRUGS

Katarzyna Kulig, Piotr Nowicki, Barbara Malawska Department of Pharmaceutical Chemistry, Medical College, Jagiellonian University, Medyczna 9, PL 30-688 Kraków, Poland

Influence of the absolute configuration on pharmacological activity of antihypertensive and antiarrhythmic drugs. K. KULIG, P. NOWICKI, B. MALAWSKA. Pol. J. Pharmacol., 2004, 56, 499–508. Chirality is a fundamental property of biological systems and reflects the underlying asymmetry of matter. Interactions of drugs with receptors, en- zymes or binding sites have long been known to be stereoselective, and it is increasingly recognized that both pharmacodynamic and pharmacokinetic events contribute to the overall clinically observed stereoselectivity. The pharmacological activity may reside only in one enantiomer, while the second one may be inactive or have desirable or undesirable activity. Two isomers may be nearly identical both in qualitative and quantitative aspects of pharmacological activity. The activity of particular enantiomers may differ only at the quantitative level. It is also possible that a particular enantiomer displays qualitatively different mode of action than the second one. This review describes the influence of the absolute configuration on pharmacological activity of the selected currently used or being under investigation drugs acting on cardiovascular system, especially as the antihypertensive and antiarrhythmic agents. Key words: chirality, absolute configuration, antihypertensive drugs, antiarrhythmic agents

correspondence; e-mail: [email protected] K. Kulig, P. Nowicki, B. Malawska

Introduction in potency between enantiomers, whereas weakly active compounds had little difference between Isomers are unique molecular entries composed enantiomers. The enantiomer with the highest ac- of the same molecular constituents with common tivity is termed after Ariëns the eutomer, while the structural characteristics. Among several subtypes one with the lowest is distomer. The eutomer/dis- of isomers, optical isomers are said to possess a “chi- tomer ratio is called the eudismic ratio [10, 21]. ral” or asymmetrical center. Term “chiral” derives Only one enantiomer may be responsible for the from the Greek term chiros meaning hand, and de- pharmacological activity of chiral drug. In this scribes a molecule, which is not superimposable on case, the other enantiomer is regarded as an inac- its mirror image (Fig. 1). The chirality fascinated tive or undesirably active impurity. Two optical scientists since the middle of 19th century, when isomers may have nearly identical both qualitative Louis Pasteur presented optical isomers of tartaric and quantitative pharmacological activity or their acid. By picking the differing crystal types, he re- activity can differ only quantitavely. Additionally, cognized that any of optical isomers polarized light an enantiomer could display adverse pharmacol- differently, and by extending this idea, the concept ogical activity [21, 38]. Differences in the activity of an asymmetrical atom was proposed by van’t of stereoisomers may be also shown in terms of Hoff and Le Bel in 1874 [5, 25]. their bioavailability, distribution, metabolic and Life and chirality are strictly connected. At a mo- elimination behavior, and can be seen everywhere, lecular level, chirality represents an intrinsic pro- where stereochemical parameters have fundamen- perty of the ‘building blocks of life’, such as amino tal significance to their action and disposition in acids, sugars, peptides, proteins and polysaccha- biological systems [17, 28, 48, 50]. rides. As a result, metabolic and regulatory pro- In this review, we present only a brief overview cesses occurring in biological systems are sensitive of different pharmacological response to selected to stereochemistry and different responses may be enantiomeric cardiovascular drugs and compounds observed when comparing the activities of enanti- being under investigation as cardiovascular agents. omers [28]. Taking the above into consideration, Its aim is illustration of potential benefits and/or enantiomeric drugs have became increasingly im- danger of using a single enantiomer in therapy of portant over the last 20–30 years. The advanced hypertension and arrhythmia. technology let synthesize enantiomerically pure Cardiovascular diseases are a reason of about compounds. In parallel, it is of interest to replace 50% of premature death in Western industrialized a drug already approved as racemate by its more countries, and, therefore, an extensive search for active enantiomer, so call ‘chiral switches’. In new and better drugs became a challenge for differ- 2001, of the $ 410 billion in worldwide sales of for- ent pharmaceutical laboratories both industrial and mulated pharmaceutical products $ 147 billion be- academic [47]. longs to single-enantiomer drugs [4, 38, 49]. Theoretical description of interaction between Adrenoceptor antagonists an enantiomer and a biological system was formu- lated by Carl Pfeiffer. He observed that highly po- Adrenoceptor (AR) antagonists are mainly used tent chiral compounds showed a larger difference for treating angina and hypertension. Agents which block the a-ARs act on the a-ARs of blood vessels, causing relaxation of smooth muscles, dilatation of mirror the blood vessels, and drop in blood pressure. A A Agents which block the b -ARs act on the b-ARs in the heart slowing down the heart rate and reducing the force of contractions. b-Blockers also have a range of other effects in other parts of body which D B B D contribute to decrease of blood pressure [14, 39]. C C a-Adrenoceptor antagonists Prazosin, the prototype of quinazoline-bearing compounds, was the first a -AR antagonist used as Fig. 1. Mirror image of a hypothetical chiral molecule an effective agent in the treatment of hypertension.

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Its pharmacological activity depends on peripheral racemic mixture and enantiomers. However, in case vasodilatation mediated by a post-junctional a -AR of a -AR, the binding affinity of (S)-doxazosin was blockade. Additionally, prazosin improves the plasma slightly lower than that of (R) enantiomer. Addi- lipid profile [22, 51, 52]. Being an achiral com- tionally, (S)-doxazosin exhibited a higher a /a -AR pound, prazosin became a very useful and interest- selectivity ratio (480–612) as compared to the (R) ing lead compound in developing new antihyper- isomer (107–140). The racemic mixture showed in- tensive agents (Fig. 2). The replacement of the termediate selectivity between its component enan- piperazine ring with decahydroquinoxaline moiety tiomers [13]. leads to optically active, potent and selective (a / Also compounds bearing benzodioxane ring a ratio 1800) prazosin analog, cyclazosin (Fig. 2). substituted at the 2-position display affinity for It was shown that (-)-cyclazosin, although more po- a -AR. The model compound of this series WB tent than (+)-cyclazosin at all subtypes of a -AR, 4101 (Fig. 3) is highly potent towards a -AR, and was nearly devoid, like parent compound, of retains significant affinity for other receptor sys- a -AR subtype selectivity, with the exception of tems such as a -AR and 5-HT ) receptors. Its enan- a 12-fold higher affinity for native a * vs. a )-AR. tiomers have different affinities for a -AR. The In addition, (+)-cyclazosin displayed high affinity (S)-WB 4101 has been reported to be much more (pKE = 9.16) for cloned a *-AR and a significantly active than the corresponding (R) enantiomer, and lower potency at both a *- and a ,-ARs (pKE = their affinities for a )-AR are 0.16 and 39.8 nM, 7.48 and 7.57, respectively). Additionaly, (+)-cycla- respectively [2, 32]. zosin displays selectivities of 1100-, 19000- and Among several analogues of WB 4101, me- 12000-fold in binding to a *-AR vs. a -AR, phendioxan, bearing p-tolyl substituent at 3-position 5-HT ) and D -receptors, respectively [32, 33]. is the most potent and selective for a -AR sub- The role of the furan moiety of prazosin was in- types. (-)-Mephendioxan was significantly more vestigated through its replacement by various rings. active at a -AR than the other optic isomer. This The compound bearing 1,4-benzodioxane ring, enantiomer was also 12000-, 2500-, 250-fold more doxazosin (Fig. 2), displayed affinity for a -AR, selective in binding to a -AR relative to a -AR, and is used for treatment of hypertension and be- 5-HT ) and D -receptors, respectively [32]. nign prostate hyperplasia (BHP). In the radioligand b binding studies using an isolated human tissue, -Adrenoceptor antagonists doxazosin and its enantiomers showed higher affin- The b-blockers comprise a group of drugs that ity for a -AR than a -AR, but no significant differ- is mostly used to treat cardiovascular disorders, ences in affinity for a -AR were observed between such as hypertension, cardiac arrhythmia or ische-

O N

CH O N N 3

N Prazosin CH3O

NH2

O O O O N N CH O N N 3 CH O N N O 3 N CH O N 3 CH O (S)-Doxazosin 3 (+)-Cyclazosin NH 2 NH 2

Fig. 2. Prazosin and its chiral analogs

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X R H CO 3 Metoprolol is a selective antagonist of b1-AR, and is used as a racemate. Its b-blocking capacity NH has been shown to reside predominantly in the O O (S)-enantiomer, whereas (R)-enantiomer does not WB 4101 X = O,R=H OCH contribute to this effect. The pharmacokinetic in- Mephendioxan X = O, R = 4-tolyl 3 vestigation of metoprolol in the rat model indicated Fig. 3. WB 4101, mephendioxan and its analogues that the estimated average t0.5 of enantiomers was similar (35 min) indicating that the rat is its ex- mic heart disease. Each of these drugs possesses at tensive metabolizer. In poor metabolizers of meto- least one chiral center residing in the alkyl side prolol, the half-life of (R)-enantiomer is longer than chain, directly attached to an OH group, and is that of (S) one [36, 45]. In poor metabolizers, it was characterized by inherent high degree of enantiose- also observed that in the pathway of metabolism, lectivity in binding to the b-ARs. Generally, for which leads to a-hydroxymetoprolol, formation of b-blockers with a single chiral center, the S-(-)-enan- a new 1’R chiral center from both enantiomers of tiomer displays higher affinity for binding to the metoprolol was favorable [6]. There were also dif- b-ARs than an antipode. The reported S:R activity ferences of bioavailability parameters (CMax, AUC) ratios are in the range from 33 to 530. Additionally, between enantiomers of metoprolol. After an ad- the enantiomers of some these drugs possess other ministration of selected formulations or racemic effects, such as antagonistic activity at a-AR or metoprolol, the AUC and CMax were always higher class III antiarrhythmic activity. However, due to for (S)-metoprolol than for its antipode [34]. economic reasons most b-blockers are used sys- Sotalol was originally recognized as a b-AR tematically or administered clinically as the race- blocker, and was subsequently discovered to have mates [30, 44]. also class III antiarrhythmic activity (potassium Propranolol is a first b-blocker which was in- channel blocker). Sotalol is a racemate, its S-(-) iso- b troduced into therapy. It was found that S-(-)-propra- mer is a blocker of both -AR and potassium chan- nolol was about 40 times more potent than the nel, while the second isomer R-(+) possesses only R-(+)-enantiomer. Additionally, the enantiomers potassium channel blocking activity. These findings offered the promise that R-(+)-sotalol would be display similar local anesthetic and antiarrhythmic better tolerated than the racemate. However, the activities. Stereoselective binding has been re- performed placebo-controlled investigation indi- ported for propranolol in whole plasma as well as cated that mortality associated with the proarrhyth- with individual serum proteins. The free fraction of a mic actions of sotalol increases after application of R-(+)-propranolol is higher in 1-acid glycoprotein its R-(+)-enantiomer [27]. (AAG). The stereoselectivity of propranolol in its Nevibolol is a b1-AR blocking drug that con- binding to human serum albumin is opposite to that tains four chiral centers. Of the ten existing stereoi- observed for AAG [30, 48]. somers, nevibolol contains equal amounts of (+)-n- b Pindolol is a non-selective -blocker, which is evibolol (S, R, R, R) and (-)-nevibolol (R, S, S, S). used in the treatment of hypertension. It is marketed The (+)-nevibolol is a potent, highly selective and as a racemic mixture of two enantiomers, and there long-acting b1-AR blocker. Isomer (-) is responsible are differences in their pharmacodynamic and phar- for the typical changes in the hemodynamic action macokinetic properties. Similarly to propranolol, the of racemate. The (-)-enantiomer at the dose that S-(-)-enantiomer of pindolol is more potent b1-AR does not lower blood pressure markedly enhances blocking agent than its antipode. It was also shown the antihypertensive activity of the (+)-enantiomer. that after oral administration of racemic pindolol, The (-)-nevibolol appears to modulate or reverse the S-(-)-pindolol achieved higher plasma concen- the negative inotropic cardiac action of (+)-form, tration level than less active R-(+)-pindolol. There and promotes nitric oxide (NO) release from endo- were also observed differences in renal excretion thelial cells [27, 29, 41]. between enantiomers of pindolol. In this case, a b a higher renal clearance was observed for S-(-)-pi- , -Adrenoceptor antagonists ndolol (14.4 L/h) in comparison to R-(+)-pindolol Labetalol (Fig. 5) is an example of pseudo- (12 L/h) [11]. hybrid drug, that is a compound which combines

502 Pol. J. Pharmacol., 2004, 56, 499–508 THE ABSOLUTE CONFIGURATION OF DRUGS

CH 3 OH

O NH CH3 O NH CH3 OH CH H C 3 3 O Propranolol Metoprolol

OH OH OH O NH O CH NH 3 CH 3

S CH3 F Nevibolol F O NH Sotalol O OH CH O NH 3

CH3

HN Pindolol Fig. 4. b-AR antagonists two pharmacological actions in the racemic mix- provement of contraction. There are three main ture. Labetalol contains two chiral centers and, groups of calcium channel blockers, i.e. dihydropy- therefore, has four stereoisomers. The racemic ridines, phenylalkylamines and benzothiazepines. mixture of labetalol is a potent antagonist of a 4-Aryl-1,4-dihydropyridines of the nifedipine type (pKE = 7.44), b (pKE = 8.31) and b (pKE = 8.10) are the most studied class of calcium channel ARs. Its b -AR blocking activity mainly resides in modulators and, since the introduction into therapy the (S, R) isomer (pKE = 7.18), while the (R, R) iso- in 1975, have became almost indispensable for mer, called dilevalol, was found to be a potent treatment of cardiovascular diseases, such as hyper- b-AR antagonist (pKE> = 8.26, pKE> = 8.52). In tension, cardiac arrhythmias, or angina. Although spite of having the advantage of not producing pos- nifedipine is an achiral agent, most dihydropyri- tural hypertension dilevalol was not introduced into dines have an asymmetric carbon atom at 4 posi- the market due to the hepatotoxicity not seen to the tion of the heterocyclic ring and are generally used same extent with labetalol [9, 48, 49]. as racemic mixtures except for barnidipine. It was Similarly to labetalol, carvedilol is a compound found that in case of these compounds the eutomers possessing a- and b-adrenergic activity, which can are usually S-enantiomers. Their eudysmic ratios be considered as a pseudo-hybrid molecule. The are in range from 2 for nimodipine to 1000 for am- a -AR blocking activity of carvedilol resides at the lodipine [15, 18]. (S)-enantiomer, while the b -AR blocking activity Amlodipine (Fig. 6) is a mixture of two enanti- is a property of both enantiomers. (R)-Carvedilol is omers, one (S) having L-type channel blocking ac- better metabolized by CYP2D6, which explains the tivity, whereas the (R)-enantiomer releases NO [53]. differences in a /b relative activities, depending Additionally, pharmacokinetics studies showed no on the genotype and expressed alleles. Carvedilol is significant differences between behavior of R-(+) also a calcium channel blocker, and sodium chan- and S-(-)-enatiomers. On the other hand, different nel modulator [20, 46]. pharmacokinetic behavior was observed for nicardipine (Fig. 6). Serum concentration of (+)-nicardi- Calcium channel antagonists pine, playing a major role in blocking calcium The key characteristic of calcium channel channel, were found to be twice higher than those blockers is their ability to inhibit entry of calcium of (-) one [15, 16, 26]. Different pharmacological ion via a subset of channels, thereby leading to im- properties were observed for enantiomers of 1,4-di-

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O OH O NH O NH H N OCH 2 3 CH 3 Carvedilol HN HO Labetalol

Fig. 5. a-, b-antagonists hydropyrimidine derivative, Bay K 8644. The S-(-) diac depressant properties, while (R)-isomer is pre- form of this compound is a calcium channel ago- dominantly a vasodilating drug. (S)-verapamil is nist, whereas the R-(+) is its antagonist [23, 48]. In also characterized by approximately double first the recent years, the interest has also been focused pass effect as compared to the (R)-antipode [35, 42, on aza-analogs of dihydropyridines, such as dihy- 48]. Gallopamil is a methoxy-derivative of verapa- dropyrimidines which possess similar pharmacolo- mil. Similarly to its parent compound, the S-en- gical activity as the parents compounds. The per- antiomer of gallopamil is responsible for cardio- formed pharmacological studies in this group have vascular and electrocardiographic effect of this demonstrated that antihypertensive effect of model drug. However, in contrast to verapamil, gallopamil SQ 32926 and SQ 32547 compounds resides in first pass metabolism is not stereoselective [12]. their R-enantiomer [19]. Diltiazem (Fig. 8), a benzothiazepine derivative Verapamil (Fig. 7), L-type calcium antagonist, that contains two chiral centers, is a voltage-depen- is a phenylalkylamine derivative. This drug is mar- dent calcium channel antagonist used in treatment keted as a racemate and is employed in treatment of of arrhythmia. It was found that (+)-diltiazem with hypertension, arrhythmia and angina pectoris. The configuration (2S,3S) is a voltage-dependent cal- enantiomers of verapamil have various pharma- cium channel and possesses ability to protect the cokinetic properties and, hence, differ in bioavail- myocardium against the injury caused by ischemia ability and pharmacological activity. The S-(-) en- or reperfusion. Its optical isomer (-)-diltiazem dis- antiomer is about 20 times more potent than the plays 20–100 times lower calcium blocking activity R-(+) in both cardiac and cardiovascular prepara- than (+) form, but like (+) isomer possesses cardio- tions. (S)-verapamil has both vasodilating and car- protective action [40].

NO NO

Cl O CH O CF H COOC COOC H H COOC N H C NO O O

H C NH CH OCH CH NH H C NH CH H C NH CH Amlodipine Nicardipine Bay K 8644 NO

CF CH O O CH O O N H C O N NH H C O N O F H C NH O H C NH S SQ 32926 SQ 32547

Fig. 6. Calcium antagonists – dihydropyridines and dihydropyrimidines

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H C CH CH H C CH CH CN 3 3 3 CN 3 3 3 O N O O N O H C CH H C CH 3 3 3 3 H C CH H C CH 3 O O 3 3 O O 3 Verapamil Gallopamil O CH 3

Fig. 7. Calcium channel blockers – verapamil and gallopamil

Potassium channel activators Sodium channel blockers ATP-sensitive potassium channel openers have One of the earliest known uses of chiral com- been shown to be a potential class of therapeutic pound to cure a disease is the case of quinine (Cin- agents for the control of cardiovascular diseases in- chona alkaloid). The first use of Chincona alka- cluding angina, hypertension and arrhythmias. Cro- loids is often attributed to the Countess Anna of makalim (Fig. 9) is the pioneer compound of this Chinchon, who reputedly was cured of an ague by class. Its hypotensive effect resides virtually exclu- Cinchona bark some time in the late 1620s or early sively in the 3S, 4R enantiomer, levocromakalim. 1630s. The stereoisomer of quinine, quinidine (Fig. However, beside the potent vasodilating effect, cro- 10), has been prescribed, since 1918 as an antiar- makalim and its enatiomer produce also significant rhythmic agent classified into Ia class according to side-effects, such as reflex tachycardia, edema, V. Williams. It is a drug, which has property of headache, and flushing [3, 24]. In order to reduce slowing conduction and also of prolongation of re- the side-effects and improve clinical potential of polarization [1, 25, 43]. that group of compounds, various modifications of Disopyramide is a class I antiarrhythmic agent cromakalim were performed. It was found that in- that exhibits concentration-dependent binding to troduction of hydroxymethyl group into 5 position plasma proteins, especially a -glycoprotein. Its of pyrrolidin-2-one ring led to the hypotensively S-(+)-enantiomer is significantly more potent than active compound (-)-MJ-451, which does not ex- R-(-) as antiarrhythmic, while the differences are hibit reflex tachycardia. It also suppresses ventricu- lesser, when their anticholinergic actions at mus- lar arrhythmias induced by myocardial ischemia carinic receptors are compared. After enantiomer and reduces infarct size after reperfusion. (-)-MJ- administration, it was found that no deference in -451 produced its cardioprotective effect without plasma clearance, renal clearance or volume of dis- affecting hemodynamic variables [24]. tribution was observed. When the racemete is given, the S-enantiomer has lower plasma and renal clearances, a longer half-life and a smaller apparent volume of distribution than those of R one. This ef- O CH fect is explained by its stereoselective binding to 3 plasma proteins and the resultant enantiomer com- petition [31, 48,]. Tocainide belongs to class I b antiarrhythmics, S and has shown stereoselectivity in action of its O enantiomers. In sodium channel activity, an (R)- tocainide is more potent than its antipode. The me- CH N 3 tabolism is also stereospecific and stereoselective O O in favor of (R)-tocainide, but only in one pathway, which is formation of glucuronide conjugate of Diltiazem N-carboxytocainide [31]. There are also known dif- H C N 3 CH ferences in elimination of tocainide enantiomers. It 3 was observed that (R)-tocainide was eliminated Fig. 8. Diltiazem faster than an opposite enantiomer. These differ-

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OH N O O N CN OH CN OH CH CH 3 3 CH O CH3 O 3 Levocromakalim (-)-MJ-451

Fig. 9. Potassium channel activators

N N HO CH CONH 3 2 O N CH 3 H3C H C CH N 3 3 Quinidine Disopyramide

OH NH CH 2 O NH 3 CH N 3 NH CH O 3 NH O CH 3 Tocainide Propafenone Cibenzoline Fig. 10. Sodium channel blockers ences were caused by different plasma concentra- lyzing ability and/or affinity to the substrate [30, tions of free fractions of enantiomers and stereose- 55]. lectivity of glomerular filtration [50]. Cibenzoline is a sodium channel blocker that Propafenone (PPF) is a chiral antiarrhythmic also exhibits potassium and calcium channel block- drug used clinically as a racemic mixture. Although ing activity. It is used as a racemic mixture but both enantiomers are equally potent in their activity S-(-)-enantiomer is approximately twice more po- as sodium channel blockers, the S-(+)-enantiomer tent that the R-(+). Additionally, its R-isomer is exhibits 100-fold higher b-blocking activity. It has preferably (about 23 times more) metabolized [37]. been demonstrated that R-enantiomer is cleared faster than S one, leading to higher concentration of Conclusion S-form in plasma after administration of racemic Many of the drugs currently in clinicall use are PPF to humans. Additionally, in vitro studies on chiral compounds. Most of them have been studied human microsomal preparations have shown that and used only as racemates. There are many race- enantiomer/enantiomer interaction between S- and mic drugs where the stereospecificity of the me- R-PPF was inhibited by (R)-PPF [7, 8, 54, 56]. The- tabolism and/or pharmacodynamic effects of the se metabolic differences occurred only at higher enantiomers are not known today. For these drugs, concentrations of drug, and their mechanism, might there is a great need for studies of these differences involve enantiomeric difference in enzymatic cata- to improve treatment of the patients.

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