Laboratory notes Novel milrinone analogs of pyridine-3-carbonitrile derivatives as promising cardiotonic agents Adnan A. Bekhit a, *, Azza M. Baraka b a Department of pharmaceutical chemistry, faculty of pharmacy, university of Alexandria, Alexandria 21521, Egypt b Department of pharmacology, faculty of medicine, university of Alexandria, Alexandria 21215, Egypt Received 2 June 2004; received in revised form 9 June 2005; accepted 15 June 2005 Available online 22 July 2005 Abstract In an attempt to design new inotropic drugs for congestive heart failure (CHF) with less proarrhythmic potential, three series of compounds analogous to milrinone were prepared, namely, 4-aryl-6-(4-pyridyl)-2-oxo-1,2-dihydropyridine-3-carbonitriles 2a–g, 4-aryl-6-(4-pyridyl)-2- thioxo-1,2-dihydropyridine-3-carbonitriles 3a–g and 2-amino-4-aryl-6-(4-pyridyl)-pyridine-3-carbonitriles 4a–g. The first series was pre- pared by reacting 4-acetyl pyridine with the appropriate aldehyde, ethyl cyanoacetate and ammonium acetate in ethanol. Reaction of 2a–g with phosphorus pentasulfide afforded the second series 3a–g. The third target compounds 4a–g were prepared applying the same procedure used to synthesize 2a–g using malononitrile instead of ethyl cyanoacetate. All the newly synthesized compounds were evaluated for their cardiotonic activity and their in vivo cardiovascular effects. In addition, their oral and parentral acute toxicity were determined. Compounds 2a, 2b, 2c, 4c and 4f proved to exert cardiotonic activity comparable to that of milrinone using spontaneously beating atria model from reserpine-treated guinea pigs. In addition these compounds proved to be non-toxic and well tolerated by mice up to 250 mg kg –1 orally and up to 125 mg kg –1 through parenteral route. © 2005 Elsevier SAS. All rights reserved. Keywords: Pyridine-3-carbonitrile; Milrinone analogs; Cardiotonics; Acute toxicity 1. Introduction Congestive heart failure (CHF) is an increasingly preva- lent problem in cardiology. The annual mortality rate of patients who have NewYork Heart Association (NYHA) func- tional class IV CHF remains high regardless of therapy with a variety of drugs [1]. Therapy with cardiotonic agents for patients who have CHF has been shown to increase cardiac output, reduce preload and afterload, and has life-saving potential [2]. Cardiotonic agents currently available for the treatment of hemodynamic crisis in CHF are cardiac glyco- sides or sympathomimetic catecholamines. Cardiac glyco- sides have an extremely narrow safety margin and high inci- dence of arrhythmogenicity [3,4]. Sympathomimetic agents (e.g. dobutamine and dopamine) are orally inactive and may lead to tachyphylaxis. Even worse is that sympathomimetic agents may increase the mortality of patients with acute CHF [5]. In the past two decades, novel non-glycosidic, non- sympathomimetic cardiotonic agents that have selective PDE III inhibitory action have been developed, e.g. amrinone [6] and milrinone [7]. In this work, we present the synthesis, characterization and biological evaluation of novel milrinone analogs, in which the 2-position of the pyridine has oxo, thioxo or amino group. The 4-position is substituted by aryl substituent, while the 5-position is unsubstituted so as to minimize the steric influ- ence upon the 4-pyridyl group in the 6-position (Fig. 1). The study aims to rationalize the effect of locating pyridyl group in the 6-position instead of methyl group in milrinone and to check how other structural modifications would influence the cardiotonic activity and cardiovascular effects of the newly synthesized compounds. 2. Chemistry Reactions outlined in Fig. 2 were adopted to synthesize the desired compounds 2a–g, 3a–g and 4a–g. Reaction of * Corresponding author. Tel.: +20 3 487 1317; fax: +20 3 487 3273. E-mail address: adnbekhit@hotmail.com (A.A. Bekhit). European Journal of Medicinal Chemistry 40 (2005) 1405–1413 www.elsevier.com/locate/ejmech 0223-5234/$ - see front matter © 2005 Elsevier SAS. All rights reserved. doi:10.1016/j.ejmech.2005.06.005