Ang Iotensin II New Class

147

Symposium

Ang iotensin II Receptor Antagonists: an Emerging New Class of Cardiovascular Therapeutics

Pieter B.M.W.M. Timmermans

Acceptance of the notion that physiologically specific interruption of the renin-angiotensin-aldosterone system (RAAS) is of considerable therapeutic benefit in the treatment of hypertension and congestive heart failure has generated great interest in the search for novel pharmacological inhibitors. The RAAS is expressed at the whole body, organ/ tissue and cellular level through the action of the octapeptide angiotensin II (Ang II), the primary effector molecule of the RAAS. The availability of selective, potent, orally active and long-acting nonpeptide Ang II type 1(AT1) receptor antagonists provided the oppor- tunity to obtain the benefits of selectively blocking the RAAS at the level of the AT1 receptor that medi- ates most, if not all, of the important actions of Ang II, and avoid the nonspecificity of the Ang I converting enzyme (ACE) inhibitors. Losartan was the first, but by no means remained the only nonpeptide AT1 receptor antagonist. Numerous other "sartans" have emerged in the past several years and successfully completed clinical development. With the exception of Eprosartan, all others, i.e. Candesartan, Irbesartan, Saprisartan, Tasosartan, Telmisartan, Valsartan and Zolasartan, are based on modifications of Losartan's prototypic chemical structure. AT1 receptor antagonists represent the newest addition to the arsenal of cardiovascular therapeutics. The predominant role of the AT1 receptor in mediating the pathophysiological role of Ang II underlies the effectiveness of this novel class of agents to lower arterial blood pressure, reduce pre- and afterload, inhibit sympathetic nervous system activity and prevent cardiovascular hypertrophy and cardiac failure induced by inappropriate control of the RAAS. (Hypertens Res 1999; 22: 147-153) Key Words: renin-angiotensin-aldosterone system, angiotensin II, angiotensin II receptors, AT1 receptors, AT1 receptor antagonists

The renin-angiotensin-aldosterone system (RAAS) renin activity (3), its therapeutic potential remained has emerged from an academically interesting, but limited, since due to its peptidic nature it has a very obscure, regulatory mechanism to an important hor- short plasma half-life, is not orally bioavailable and mone pathway know to play a pivotal role in the still possesses significant Ang II-like agonistic prop- regulation of blood pressure and fluid and electro- erties. Nonetheless, saralasin showed that the prin- lyte homeostatis (1). Activation of the RAAS is crit- ciple of interfering with Ang II at the level of its re- ically involved in the development and mainte- ceptor had therapeutic potential. nance of hypertension and congestive heart failure. The octapeptide angiotensin II (Ang II) is the pri- Despite considerable efforts, there had been little mary mediator of the RAAS. Its actions are mediated progress in the development of nonpeptide Ang II by specific surface receptors on the various target receptor antagonists until the publication of two pa- organs. The most specific and direct way to inhibit tents granted in 1982 to Furukawa and colleagues at the RAAS is by antagonism of the effector hor- Takeda Chemical Industries (4, 5). They disclosed a mone Ang II at the level of its target receptors. In series of small-molecule imidazole analogues (see theory, Ang II receptor antagonists would be able below) possessing Ang II antagonistic properties. to completely and selectively inhibit the RAAS in- Additional studies showed that although the poten- dependently of the source of Ang II. cy of these nonpeptide molecules was very moderate, the oral bioavailability very limited and the Even before the appearance of Ang I converting duration of action very short, they behaved as selec- enzyme (ACE) inhibitors, pharmacological inhibi- tive and competitive Ang II receptor antagonists tion of the RAAS was achieved in 1971 with sarala- without agonistic properties (6). These low-molec- sin, the first specific peptide antagonist of Ang II ular-weight imidazole compounds were adopted as (2). Although saralasin reduced arterial pressure in leads for further optimization. Structural modifica- hypertensive patients with high circulating plasma tion provided important chemical features that led

From the Pharmacology and Preclinical Development Department, Tularik Inc., California, USA. Address for Reprints: Pieter B.M.W.M. Timmermans, Ph.D., Tularik Inc., Two Corporate Drive, South San Francisco, CA 94080, USA. Received October 31, 1998. 148 Hypertens Res Vol. 22, No. 2 (1999)

to increasingly more potent and eventually orally AT1B), and does not possess significant affinity for active nonpeptide Ang II receptor antagonists. the so-called AT2 receptor for which PD 123,177, These activities culminated into the discovery of PD 123,319 and CGP 42112A exhibit high and losartan (7), the first clinically useful nonpeptide selective affinity (10). Virtually, if not all of the Ang II receptor antagonist, followed by eprosartan known actions of Ang II could be blocked by losar- (8) . Numerous other "sartans" were subsequently tan, emphasizing the major role of the AT1 recep- created based on modifications of losartan's prototyp- tor subtype in mediating the patho (physiological) ic chemical structure (9). actions of this hormone (11). It also clearly explains why most of the pharmaceutical effort has been fo- Losartan and nonpeptide spinacine-derived com- cused on developing nonpeptide AT1 receptor-selec- pounds, such as PD 123,177 and PD 123,319 along tive antagonists. with peptides, such as CGP 42112A, have firmly established the concept of Ang II receptor heter- As indicated above, the origin of the current potent ogeneity and have provided critical probes for the nonpeptide AT1 receptor antagonists, of which isolation and cloning of the two receptors for Ang losartan is the prototype, can be traced back to the II characterized in mammals, including man. Takeda series of 1-benzylimidazole-5-acetic acid de- According to current nomenclature, losartan repre- rivatives, such as S-8307 (CV2947) and S-8308 sents the prototype antagonist of the Ang II type 1 (CV2961) (Fig. 1) (4, 5). Losartan (7) and eprosar- (AT1) receptor family (further subtypes of rat and tan (8) were derived from this benzylimidazole mouse AT1 receptors are designated AT1A and series using two different molecular models of puta-

Fig. 1. Structural modifications of the initial lead compounds, 5-8307 (CV2947) and 5-8308 (CV 2961) which led to the successful discovery of the nonpeptide AT1 receptor antagonists losartan and eprosartan. Timmermans: AT1 Receptor Antagonists 149

Fig. 2. Chemical structures of AT1 receptor antagonists. tive active conformations of Ang II to align the as bioisosteric replacements for the carboxylic acid Takeda derivatives with the C-terminal region of group. This effort culminated in the identification of Ang II. The first modeling strategy gave rise to the AT1-selective antagonist, losartan, in which a EXP 6155 (Fig. 1) which showed a 10-fold increase tetrazole moiety substitutes for this carboxylic acid in binding affinity. From this starting point a series functionality (Fig. 1). of phthalamic acids and related compounds were synthesized with progressively higher affinity for the In many animal species as well as in man, losartan AT1 receptor. EXP 6803 exemplified this approach is metabolized to E3174, the imidazole-5-carboxylic which produced another 10-fold enhancement in acid, resulting from oxidation of the imidazole 5- binding affinity. hydroxymethyl group. Like losartan, E3174 is a However, all the compounds were virtually de- selective AT1 receptor antagonist, but is appreciably void of oral activity, until the amide linker was re- more potent and possesses a much longer duration placed with a single bond, which resulted in EXP of action (12). Like losartan, E3174 has served as a 7711. This biphenyl derivative had only slightly less template for the development of many other AT1 affinity for the AT1 receptor than EXP 6803, but receptor antagonists. represented a breakthrough to orally active conge- ners. To further improve the oral activity and dura- A different modeling approach assisted in the tion of action of these biphenyl compounds, a num- synthesis of eprosartan (8) which is representative ber of acidic groups were systematically evaluated of one of the few AT1 receptor antagonists designed 150 Hypertens Res Vol. 22, No. 2 (1999)

Table 1. Affinity for AT1 Receptors, Mode of AT1 Receptor Antagonism and AT1 Receptor Off-Rate of AT1 Receptor Antagonists (For Discussion, See Text)

independently from the Takeda benzylimidazoles substituents at the imidazole C4 and C5 positions to and not from losartan. A combination of molecular yield ring-fused imidazoles. The benzimidazole, can- modeling and knowledge of the structure-activity re- desartan cilexetil (Fig. 2), is an ester carbonate lationship for Ang II-like peptides resulted in a 15- prodrug which is rapidly converted in viva to the fold enhancement in binding affinity by chain exten- corresponding 7-carboxylic acid candesartan (15). sion at the imidazole-5-position via a trans-5-acrylic acid group followed by addition of an a-benzyl Potent antagonists have also been obtained by re- group which appeared to better mimic the Phe8 side placing the imidazole of losartan with six-membered chain in Ang II. Replacement of this a-benzyl ring and fused six-membered ring heterocycles. An group with a 2-thienylmethyl moiety followed by re- example is the AT1 receptor antagonist tasosartan placement of the 2-chlorobenzyl group with a 4-car-b (Fig. 2) (16). The enol metabolite, enoltasosartan, i oxylbenzyl group to better mimic the phenolic s responsible for the long pharmacodynamic action moiety of Tyro resulted in eprosartan (Fig. 1). of the drug (17). Eprosartan is a potent, AT1-selective antagonist. Telmisartan (Fig. 2) incorporates a carboxylic acid Losartan (E3174) was the first, but by no means as the biphenyl acidic group. Unlike the case in remained the only potent, selective, orally active other series of antagonists, the biphenylcarboxylic and clinically useful nonpeptide AT1 receptor antag- acid telmisartan was more potent than its tetrazole onist. Numerous other antagonists have successfully analog. Telmisartan is a potent, selective AT1 re- completed clinical development and have been (will ceptor antagonist (18). be) approved and marketed for the treatment of hypertension and some for congestive heart failure. In zolasartan (Fig. 2), the "spacer" phenyl ring of The number of products within this class will E3174 is replaced by a bromobenzofuran. The pres- undoubtedly further increase. ence of the 3-bromo substituent is essential for high AT1 receptor affinity exhibited by this series of Valsartan (Fig. 2) represents a nonheterocyclic AT1 compounds. Zolasartan is a potent, selective AT1 receptor selective antagonist in which the imidazole receptor antagonist possessing long-lasting anti- of losartan is replaced with an acylated amino acid. hypertensive effects in laboratory animals (19). This antagonist is a diacidic compound, like E3174 (13). In saprisartan (Fig. 2), the imidazolecarboxylic acid of zolasartan was replaced by a neutral imidazole- A number of additional antagonist designs have 5-carboxamide in order to enhance oral bio- replaced the substituted imidazole found in losartan availability. This strategy was combined with the re- with various five-membered ring heterocycles. The placement of the tetrazole with a triffamide. Sapri- potent AT1 receptor antagonist irbesartan (Fig. 2) sartan has high affinity for the AT1 receptor and its incorporates an imidazolinone ring in which a car- oral bioavailability in animals and man exceeds that bonyl group functions as a hydrogen bond acceptor of zolasartan (20). in place of the hydroxymethyl group of losartan (14). Table 1 lists the affinity of the various AT1 receptor antagonists for the AT1 receptor determined by Potent antagonists have been obtained by joining radioligand binding displacement experiments. The Timmermans; AT, Receptor Antagonists 151

Table 2. Characteristics of AT 1 Receptor Antagonists in Clinical Practice in the Treatment of Patients with Mild to Mod- erate Hypertensiona

binding affinity is reported as an average value of lished in the interval between addition of the agon- several published independent measurements using ist and development of the response in the tissue membrane preparations from different tissues. All which is usually less than 1 min (22). The most values are expressed relative to the most potent common mechanism of insurmountable antagonism antagonist (affinity=1). Candesartan and saprisar- is irreversible, covalent binding of the antagonist tan possess the highest affinity for the AT1 receptor with the receptor. The receptor number is effective- followed by zolasartan and irbesartan, the affinity of ly reduced to the point where the receptor reserve which is 3- and 5-fold less, respectively. Valsartan, is exhausted and a full agonist response can no lon- telmisartan and E3174 (the active metabolite of ger be obtained. However, there are kinetic condi- losartan) show comparable affinities that are 10-fold tions under which antagonists that do/ can not chem- less than those of candesartan and saprisartan. ically react with the receptor protein produce in- Losartan's affinity for the AT1 receptor is approx- surmountable antagonism (see 23) . This is observed imately 5 times less than that of E3174, whereas the for antagonists that slowly dissociate from the re- concentration of eprosartan has to be 100-fold high- ceptor and therefore the agonist cannot reach er than that of candesartan to occupy the same equilibrium with the antagonist/receptor complex number of AT1 receptors. Finally, the prodrug can- under the time constraints of the experiment. The desartan cilexetil has a very moderate AT1 receptor more rapid the antagonist can adjust to the pres- binding affinity. ence of the agonist the more surmountable (competitive) the antagonism becomes. It is very likely Effects of AT1 receptor antagonists on the dose/ that slow dissociation kinetics from the AT1 recep- concentration-response curves of Ang II have been tor of AT1 receptor antagonists underlie insurmount- characterized as either surmountable or competitive able antagonism. As Table 1 shows, all noncom- (i(e. , the antagonist produces a dose/ concentration- petitive AT1 receptor antagonists have a slow off- dependent, parallel shift to the right of the dose/ rate from the AT1 receptor and all competitive in- concentration-response curve of Ang II without a hibitors dissociate fast from the AT1 receptor pro- change of the maximally attainable response) or in- tein. In addition, in radioligand binding displace- surmountable or noncompetitive (i. e. , the antago- ment assays in which much more time is allowed to nist produces a dose/concentration-dependent, non- approach equilibrium than feasible in functional stud- parallel shift to the right of the dose/ concentration- ies, all AT1 receptor antagonists show (close to) response curve of Ang II accompanied by a pro- competitive antagonism of Ang II binding. gressive doselconcentration-dependent decrease of the maximally attainable response) (21) . Vasopres- The mode of AT1 receptor antagonism (competi- sor responses in vivo and vasoconstrictor effects in tive vs. noncompetitive) most probably does not vitro to Ang II have been studied to document this play a role in defining the antihypertensive effect of distinction. Accordingly, losartan, tasosartan and the antagonists. Under those circumstances the eprosartan have been classified as competitive AT1 antagonist has ample time (hours!) to reach equilib- receptor antagonists, whereas candesartan, saprisar- rium. It is therefore very unlikely that noncompeti- tan, zolasartan, irbesartan, valsartan, telmisartan tive AT1 receptor antagonists are more efficacious and E3174 behave as noncompetitive antagonists antihypertensive agents than competitive antagon- (Table 1). In order for true surmountable antagon-i ists. The extensive preclinical experience with AT1 sm to occur it is assumed that complete equilibrium receptor antagonists clearly documents similar anti- between agonist, antagonist and receptor is estab- hypertensive/hypotensive efficacies (11). However, 152 Hypertens Res Vol. 22, No. 2 (1999) the slow off-rate from the AT1 receptor exhibited the availability of positive end-point data from by several antagonists may extend the time of occu- several large trials that are currently ongoing with pancy of the receptor protein and lengthen the these agents. AT1 receptor antagonists represent a duration of the antagonism. Table 2 summarizes new milestone in the development of cardiovascular some characteristics of AT1 receptor antagonists therapeutics and add another dimension to the currently available. Interestingly, eprosartan is arcenal of drugs manipulating the RAAS. dosed twice daily and represents the only antagonist that is competitive/dissociate fast from the AT1 re- Acknowledgements ceptor and does not produce an active (noncompetitive) metabolite. 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