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Cardiovascular Effect of Pyridazine Derivative Pimobedan and Other Related Compounds Mohammad Asif*

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Cardiovascular Effect of Pyridazine Derivative Pimobedan and Other Related Compounds Mohammad Asif* American Journal of Pharmacology and Pharmacotherapeutics Review Article Cardiovascular Effect of Pyridazine Derivative Pimobedan and Other Related Compounds Mohammad Asif* Department of Pharmacy, GRD (PG) IMT, Dehradun, 248009 Uttarakhand, India *Corresponding author e-mail: [email protected] A B S T R A C T The pyridazine ring is present in various biologically active compounds and some pyridazine compounds have been reported as valuable cardiovascular agents. Benzimidazole-pyridazinone compound, 4,5-dihydro-6-[2-(4-methoxyphenyl)-1H-benzimidazole-5-yl]-5-methyl-3(2H)- pyridazinone (pimobedan or vetmedin) is a potent cardiovascular agent. It is a non adrenergic, non-glycoside inotropic drug with vasodilator activities and exerts a stimulatory myocardial activity by a dual mechanism of action with raise in calcium sensitivity of cardiac myofilaments and inhibition of phosphodiesterase. Pyridazine is an attractive compound for designing and development of novel pyridazine compounds as cardiotonic agents in future. Keywords: Pimobendan, cardiovascular, vasodilatative, phosphodiesterase, calcium sensitiser. INTRODUCTION Nowadays cardiovascular diseases and dyspnoea3. This results from myocardial (CVD) are major public health problem ischaemia (MI), arrhythmias, non- wordwide, in this regards ischemic heart compliance with treatment or intercurrent disease (IHD) or coronary heart disease infections. Acute heart failure (AHF) may (CHD) is more common.1 The prevalence is also arise suddenly following a cardiac increasingly occurs in the elderly insult in a patient without previous evidence population.2 The common cause is coronary of overt CVD. About 15% of worldwide artery disease (CAD), either alone or in mortality is attributable to heart disease combination with hypertension. Other (HD)4. It is estimated that HD will be the factors, likes hypercholesterolaemia, biggest cause of disease burden worldwide diabetes mellitus, obesity and smoking may By 20205,6. The IHD is the most important raise the risk of rising this syndrome. and most common contributor to the Indications of heart failure (HF) contain development of HF.7,8 Treatment with fatigue, anorexia, limited exercise tolerance, positive inotropic agents is indicated for American Journal of Pharmacology and Pharmacotherapeutics www.pubicon.in Ali _________________________________________________________ ISSN 2393-8862 patients with severe chronic or acute HF to are numerous essential objectives in the recover the pump function of the heart.9,10 dealing of HF: enhancement of the force of The β-adrenergic agonists and cardiac contraction, decrease of the phosphodiesterase (PDE) inhibitors improve resistance to ejection of blood from the cardiac contractility by increasing ventricles, decrease of the pre-load, i.e. the intracellular Ca2+ concentration. The end-diastolic ventricular filling volume, mechanism, leads to increase in myocardial reversal of the procedure of ventricular oxygen consumption (MOC) and increase in remodeling and restoration of the atrial oxygen demand further leads to the increase involvement to ventricular filling. of arrhythmic and ischaemic difficulties, Optimization of therapy is of utmost value which can occur in ischaemic patients, to improve signs and quality of life. whose haemodynamics is unbalanced. These drugs have not been commonly used in Phosphodiesterase inhibitors patients with ischaemia.11,12 Pimobendan Phosphodiesterase(PDE)-3 inhibiting and levosimendan drugs possesses a novel drugs (milrinone, amrinone and enoximone) mechanism of positive inotropy. These are raise contractility by decreasing the Ca2+ sensitizer agents, augments myocardial degradation of cyclic adenosine contractility by raising myofilament monophosphate (cAMP). They decreases sensitivity to Ca2+ by binding to cardiac both preload and afterload via vasodilation. troponin C in a Ca2+-dependent manner.13-15 The haemodynamic consequences of this This mechanism allows the positive action are reduced LV after load, increased inotropic effect without increasing cardiac output and reduced total peripheral intracellular Ca2+ concentrations. resistance (PR). Distinct from Pimobendan and levosimendan also opens sympathomimetic amines, PDE-3 inhibitors ATP-sensitive K+ channels (K+ ATP) in generate no tolerance and possess the vascular and cardiac muscle, thereby distinct benefit of directly reducing generating vasodilator and also anti- pulmonary vascular resistance.24-28 Low- ischaemic effects.16-18 Pimobendan and dose oral enoximone has been evaluated in levosimendan are inhibited cardiac and some clinical trials, mainly its effects during smooth muscle PDE.19,20 co-administration with β-blockers.29,30 Other drug, vesnarinone, a mixed PDE inhibitor MANAGEMENT OF CHRONIC and ion-channel modifier has modest, dose- HEART FAILURE dependent, positive inotropic effects, but minimum negative chronotropic activity, has The decline in the effective superior haemodynamics and quality of functioning of the heart as a pump life.31-33 characterises the syndrome of HF. It generally happens as a outcome of left Calcium sensitizers ventricular systolic dysfunction (LVSD) The positive inotropic agents act by (decreased contraction), although diastolic 21 increasing the sensitivity of troponin C or dysfunction (raise ventricular stiffness). some other part of the myofibrillar Ca2+– The complex reflex actions that are initiated binding. There are several drugs with to increase cardiac output (CO) in the failing reported calcium sensitizing properties (eg. heart eventually supply to additional cardiac sulmazole, isomazole, adibendan, dysfunction. Left ventricular (LV) pump meribendan, etc), but most of the clinical failure results in reduced blood pressure data come from two compounds: (B.P) and reduced renal perfusion.22,23 There AJPP[1][3][2014] 093-104 Ali _________________________________________________________ ISSN 2393-8862 pimobendan and levosimendan. Pimobendan systolic pressure (LVSP) (-5 to -45%), left is a calcium sensitizer with PDE-3 inhibitor ventricular filling pressure (LVFP) (-20 to - properties. Both intravenous and oral 40%) but had only a slight effect on the formulations have been studied in patients highest rate of rise of left ventricular with HF. Intravenous bolus doses had clear pressure (LVP) (10-20%). The decrease in inotropic, vasodilatory and chronotropic mean arterial B.P was primarily due to effects in patients with HF, increasing CO systemic vasodilation; PR and CO decreased and reducing systemic vascular resistance by up to 40 and 14%, respectively. (SVR) and LV end-diastolic pressure.34,35 In Vasodilation occurred in several vascular comparison with captopril, pimobendan beds, but was particularly pronounced in the appeared to be a stronger arterio- adrenals, stomach, small intestine and venodilator.36 The effects of oral myocardium. Although the increase in pimobendan were similar to those seen after myocardial blood flow favoured the I.V administration.37,38 Pimobendan epicardium, vascular conductance in both increased exercise duration and peak oxygen the endo- and epicardial layers was uptake 39-41. The efficacy and safety were significantly increased. Myocardial oxygen similar to those seen with enalapril, although consumption (MOC) was not influences a some what higher incidence of arrhythmias despite the raise in heart rate. However, in was seen42,43. In contrast, pimobendan animals where max LVP and CO were significantly less morbidity and better the reduced and pre- and/or after-load were physical activity of patients with stable HF increased by partial occlusion of the left without raise in adverse cardiac procedures. anterior descending coronary artery, Therefore, the role of pimobendan in the pimobendan clearly increased both max treatment of HF remains to be clarified and LVP and CO. Pretreatment with propranolol adequately powered prospective long-term did not modify any of the cardiovascular mortality/morbidity trials are warranted in responses to pimobendan, thereby excluding that value. the involvement of a β-adrenoceptor mechanism. Pimobendan is thus a BIOLOGICAL ACTIVITIES OF compound with vasodilator and positive PYRIDAZINE ANALOGUES inotropic properties that improves CO in animals with severe MI. The finding that the Recently, a great attention has been mild tachycardia caused by pimobendan was focused on pyridazine analogues for their not accompanied by an increase in MOC wide-spectrum pharmacological activities. warrants investigation to evaluate its Different structural alterations were carried usefulness in the treatment of HF.46 out in pyridazine ring system. These The pimobendan exhibited positive structural modified compounds resulted in inotropic effect. The acute systemic different type of fruitful biological activities. hemodynamic effects of Ca+2 antagonist Large number of pyridazine analougues are 44,45 pimobendan, a PDE inhibitor with well known as cardioactive agents. vasodilating as well as positive inotropic properties, were studied in awake pigs with CARDIOVASCULAR ACTIVITIES chronic HF. Left ventricular (LV) dysfunction, manifested by a 25% decrease Intravenous (I.V) infusions of in cardiac output (CO), a 35% increase in pimobendan, in pigs with normal coronary SVR, and a doubling of the LVFP, was circulation caused dose-dependent changes induced by a proximal ligation of the left in heart rate (10-35%), left ventricular AJPP[1][3][2014] 093-104 Ali _________________________________________________________ ISSN 2393-8862
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