Receptors in cardiovascular disease: review and introduction

PHARMACEUTICA ACTAHELVETIAE ELSEVIER

Pharmaceutica Acta Helvetiae 74 (2000) 157-161 www.elsevier.com/locate/pharmactahelv

Receptors in cardiovascular disease" review and introduction Amedeo Leonardi *, Giorgio Sironi, Gianni Motta Pharmaceutical R&D Department, Recordati, Via M. Civitali 1, Milan 20148, Italy

Abstract Despite recent encouraging declines, cardiovascular disease (CVD) is still responsible for about 50% of premature death in the Western industrialized countries, greater than cancer, AIDS and accidents, combined. Different aspects of the disease have been considered and the main currently available and possible future drugs whose effect is based on interaction with a receptor have been reviewed. Catecholamines receptors ligands, mainly [3-blockers, and the new angiotensin II antagonists represent the most important classes among the established therapies. Investigational approaches such as the oral glycoprotein GPIIb/IIIa antagonists and endothelin, adenosine and neuropeptide Y receptors ligands are discussed. Receptorology represents just a part of the therapeutical approach to CVD, where other classes of drugs with enzyme or ionic channel based mechanisms are largely used and innovative therapies based on the most advanced research techniques could early become reality. 9 2000 Elsevier Science B.V. All rights reserved. Keywords: Cardiovascular disease; [3-blockers; Mixed mechanism; Angiotensin II; Glycoprotein GpIIb/IIIa; Endothelin (ET)-I; Adenosine; Neuropeptide

Y

1. Introduction Despite the significant progress made in preventing and treating cardiovascular disease (CVD), it still is the leading cause of death in the developed world, and death due to CVD is increasing in these nations. Approximately 130 million people in the seven major pharmaceutical markets (the United States, Japan, France, Germany, Italy, Spain and the United Kingdom) suffer from CVD. In 1995, approximately 2.6 million people in these countries died from CVD. Diseases of the heart and vascular system encompass a variety of conditions, the most relevant of them being strictly interrelated, as show in Fig. 1. Hypertension and atherosclerosis are central to the pathogenesis of coronary artery disease (ischemia, angina, myocardial infarction) heart failure, cerebral (stroke) and peripheral vascular disease. Since these two risk factors have been widely investigated in the last years, many different therapeutic approaches are now available, in particular for hypertension, and this is reflected in the conspicuous market share

* Corresponding author. Tel.: +0039-2-48787-408; fax: +0039-24870-9017; e-mail: [email protected]

foreseen for them for the end of 1999, as shown in Table 1. The search for new approaches in the field of hypertension and atherosclerosis is still of interest; also if a major research investment is being devoted to the other conditions of CVD and, in particular, to their prevention. It is interesting to remark that the total cardiovascular market has been US$65 billion in 1998 and that 48 out of the top 50 pharmaceutical companies have research projects in the CVD field.

2. Receptors as therapeutic targets in CVD The main established, marketed therapeutics, having a receptor as their target, are shown in Table 2, subdivided by classes and paired to the investigational approaches (Fig. 2) in the same classes, encompassing some representative new drug candidates at different development levels. Among the oldest established therapies, catecholamine receptor ligands are the most important, with the [3-blockers as the major class. Although ~ - b l o c k e r s have been in use for a long time, their mechanism of action in hypertension is uncertain yet, although a number of possible mechanisms are likely to be involved. There are many [3-blockers now available and

0031-6865/00/$ - see front matter 9 2000 Elsevier Science B.V. All rights reserved. PII: S0031-6865(99)00029-1

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A. Leonardi et al. / Pharmaeeutica Acta Helvetiae 74 (2000) 157-161

RENALDATMAGE~

ANGINA~

MI* ~ "

CEREBRALi AMAGE(STROKE)

HEART ~ FAILURE

LV HYPERTROPHY

ARRHYTHMIA 9MYOCARDIAL INFARCTION

Fig. 1. Cardiovasculardisease map.

their clinical use is based on three main characteristics: cardioselectivity, intrinsic sympathomimetic activity (ISA) and lipid solubility. Despite these differences, they are approximately equipotent as antihypertensive agents and the choice should be oriented toward cardioselective agents with ISA and low lipophilicity, offering the likelihood of minimizing side effects and poor interaction with lipid and carbohydrate metabolism upon once-a-day administration (Kaplan, 1997). Furthermore, the antiarrhythmic (class II) and antianginal effects of these drugs make them especially valuable in hypertensive patients with coexisting coronary disease. Mixed mechanism adrenergic agents are also in use as antihypertensives, like oL+ [3 adrenoceptor blockers, the most known being labetalol and carvedilol, which probably by virtue of its additional antioxidant activity is being used also for prevention and therapy of heart failure (Lowes et al., 1999). Other mixed mechanism drugs used in hypertension are the OLz-adrenergic + imidazoline 11 agonists (clonidine, guanfacil, rilmenidine, moxonidine) and the c~1-adrenergic + 5-HT 2 serotonergic antagonist, ketanserin. A new compound of this type has been recently reported (SUN 9221) (Mizuno et al., 1999). Also the oL1-adrenergic + Ca 2+channel blocker agents, monatepil (Honda et al., 1995) and S-2150 (Kimoto et al., 1997), have shown interesting results in animal models. The only receptor-targeted antihypertensive drugs in the renin-angiotensin system (RAS) are the antagonists of the angiotensin II (AT1) receptor. Angiotensin II is the final active component in the RAS and plays a major role in the regulation of blood pressure and renal function by interacting with the AT~ receptor, the AT 2 type being possibly involved in foetal/early live and wound healing (Reid, 1996). After the good results obtained in hypertensive patients with saralasin, a peptide analog of angiotensin II with partial agonist activity (Nicholls et al., 1994), many laboratories were involved in the search for non-peptidic antagonists of the AT~ recep-

tors and the first marketed drug of this class, losartan, has been followed by some others, with further compounds in final development stages. Angiotensin II antagonists confirmed the better side-effects profile expected by lack of interaction with the kallikrein-kinin-prostanoids system but in some cases, limited efficacy was shown and several associations with diuretics and Ca 2+ antagonists are under evaluation. Glycoprotein G P l l b / I l l a antagonists currently available for intravenous use as antithrombotics following coronary angioplasty (PTCA) represent a recently introduced class of drugs and contain one of the few monoclonal antibodies used as therapeutic, abciximab. Coronary thrombosis is largely platelet-dependent, through platelet adhesion, activation and aggregation. Aspirin and ticlopidine predominantly target platelet activation pathways but because of the variety of means through which platelet can be activated, the blockade of any single platelet activation pathway can have limited efficacy. The final, obligatory step in the formation of platelet aggregates is the cross-linking of platelets by plasma fibrinogen, or other matrix proteins. This process is mediated by the GPIIb/IIIa receptor located in the platelets, which becomes competent to bind fibrinogen upon platelet activation (Abrams and Shattil, 1997). Several antagonists of the platelet GPIIb/IIIa receptor endowed with oral activity are currently undergoing clinical studies (Olson et al., 1999) and their availability will surely help to lower the risk of thrombotic events in unstable angina and following PTCA.

3. Investigational approaches based on receptors Endothelin (ET)-I is the most potent vasoconstricting and hypertensive agent so far reported. It is produced by endothelial cells and targets with the same affinity two receptors: ETA and ET B, which are located in smooth muscle and endothelial cells of the vascular system and myocardium (Quadri et al., 1998). Several nonpeptidic antagonists selective for the ET-A are under evaluation mainly for their potential use in primary pulmonary hypertension, a lethal disease without

Table 1 Distribution by value of the current CVD therapies Cardiovascular agents Market share (%) Antihypertensives 50 Vasodilators 6 Hypolipidemics-antiatherosclerosis 20 Anticoagulants 12 Cardiac stimulants 3 Antiarrhythmics 4 Othersa 5 aCardiovascular shock, cardiac protectants.

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Table 2 Main receptors in cardiovascular disease Drug class

Established targeted receptor

Drug

Investigational approach

Compound

Antihypertensives

[3-adrenergic antagonists [3-adrenergic antagonists (ISA)

propranolol, nadolol, timolol pindolol, carteolol, penbutolol

adenosine A~ antagonists endothelin A antagonists

[31-adrenergic cardioselective antagonist (no ISA) e~~-adrenergic antagonists

bevantolol, metoprolol, atenolol

neuropeptide Y antagonists

KW-3902 LU135252, TBC 11251, PD 163070 BIBP-3226

prazosin, terazosin, doxazosin

c~1-adrenergic + Ca 2+-channel antagonists

Monatepil, S-2150

oL+ [3-adrenergic antagonists 2-adrenergic + imidazoline I I agonists oL~-adrenergic + 5-HT 2serotoninergic antagonists dopamine D~ agonists angiotensin II-AT~ antagonists

labetalol, carvedilol clonidine, guanfacil, rilmenidine, moxonidine ketanserin

o~1-adrenergic + 5-HT2 antagonists

SUN-9221

adenosine A2 agonists (?)

CGS 22989

adenosine A 1 agonists glycoprotein IIb/IIIa antagonists

CVT-510 lefradafiban, sibrafiban, xemilofiban ramatroban, bosentan, SB 209670 GP-531

Coronary vasodilators Antianginal Hypertensives Antiarrhythmics Inhibitors of platelets function

aldosterone antagonists oL1-adrenergic antagonists

fenoldopam losartan, valsartan, irbesartan, eprosartan, candesartan spironolactone prazosin

[3-adrenergic antagonists oL-adrenergic agonists dopamine agonists [3-adrenergic antagonists glycoprotein IIb/IIIa antagonists

atenolol, acebutolol ephedrine, metaraminol dopamine acebutolol, propranolol abciximab, eptifibatide, tirofiban

Heart failure

established therapy (Prie et al., 1997), and their potential is being evaluated also as antihypertensives. In addition to its hypertensive action, ET-1 also exerts long-term negative effects such as hypertrophy and cellular injury in myocytes in the myocardium where both ET-A and ET-B receptors are present. In the failing heart, the production of ET-1 is markedly increased and long-term treatment with ET-1 antagonists greatly improved survival rate in different animal models of chronic heart failure. Whether ET-A-selective or dual ET-A/B antagonists could be better for the treatment of heart failure still has to be clearly defined (Miyauchi and Goto, 1999). Adenosine has many cardiovascular effects that lead to vasodilatation and hypotension accompanied by cardiac depression. The research in this field led to the discovery of different subtypes for these agonists and evolved toward the study of subtypes-selective agonists and antagonists. Due to the presence of the A 2 subtype in the coronary arteries, where adenosine exerts a vasodilator effect, the search for selective A 2 agonists was very intensive and produced many candidates, but most of them were discontinued (Quadri et al., 1998). Selective A~ antagonists, such as KW-3902, have shown potent diuretic activity and other compounds of this class

TxA 2 + PGH 2 antagonist endothelin antagonists (A or A + B?) adenosine agonist

are under clinical development for different cardiovascular indications. An adenosine A 1 agonist, CVT-510, is in clinical trials for use as an antiarrhythmic and another imidazole derivative with agonistic properties, GP-668, has shown interesting cardioprotective properties (Kurz et al., 1997). Neuropeptide Y (NPY) is one of the most abundant neuromodulatory peptides with potent effects on blood pressure homeostasis through both central and vascular sites of action. At least six subtypes of the NPY receptor have been so far identified, with Y1 as the subtype mainly involved in blood pressure control (Quadri et al., 1998). Peptide and non-peptide antagonists of the NPY~ receptor are available and all of them counteract the hypertensive effects of NPY but not of other mediators such as noradrenaline and AGII. Whether NPY 1 antagonists could become general-use antihypertensive drugs still has to be clarified. Receptorology played and is playing a relevant role in CVD moving from [3-blockers to newer approaches. It must be, however, emphasized that the classes of drugs currently most frequently used in CVD have different mechanisms, namely, they are inhibitors of several enzymes such as ACE, HMG-CoA reductase, COX, carbonic

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A. Leonardi et a l . / Pharmaceutica Acta Helvetiae 74 (2000) 157-161

H2 H2N" ~ /

~

~'""~,,,., H 0

Lefradafb ian

, , O , v , COOE,

--

~

Xemilofiban

H2

~.

I~H

MeO~~UOH

Ramatroban H ~

3H3C

Bosentan.~,~F

H2

H

NH2

H~ ~

Monatepil

GP-531 HaC~ Me~~N~~I

MeO

H

CH3

SUN-9221

S-2150

H3

~

C

~H3

H MeNo ~" ~v' 1 3 H 3

LU135252

PD163070

TBC11251 H OH H

BIBP-3226 Fig. 2. Compounds under investigation approach.

anhydrase, PDE or ion channels modulators like the blockers of the Ca 2+, Na + or C1- channels or activators of the K § channels.

Furthermore, enzymes are utilized as life-saving drugs such as streptokinase or tissue plasminogen activator (TPA) in myocardial infarction, and mucopolysaccharides such as

A. Leonardi et al. / Pharmaceutica Acta Helvetiae 74 (2000) 157-161

heparins and also monoclonal antibodies are in use or under evaluation in cardiovascular shock.

4. Conclusion The classical receptorial approach is just a part of the research in CVD, where the search for new biological targets by use of the most advanced techniques is a reality and will yield innovative therapies in the future.

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