Pharmacological Effects of ATI22-107 [2-(2-{2-[2-Chloro-4-(6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-phenoxy]-acetylamino}-ethoxymethyl)-4-(2-chloro-phenyl)-6-methyl-1,4-dihydro-pyridine-3,5-dicarboxylic Acid Dimethyl Ester)], a Novel Dual Pharmacophore, on Myocyte Calcium Cycling and Contractility

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 312; no. 2; pp. 517 - 524
• Main Authors: Jung, Albert S, Quaile, Michael P, Mills, Geoffrey D, Bednarik, Daniel P, Houser, Steven R, Margulies, Kenneth B
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.02.2005
• Subjects: 3',5'-Cyclic-AMP Phosphodiesterases - metabolism; Aniline Compounds; Animals; Calcium - metabolism; Calcium Channels, L-Type - drug effects; Calcium Signaling - drug effects; Cardiotonic Agents - pharmacology; Cats; Cell Separation; Cyclic Nucleotide Phosphodiesterases, Type 3; Dose-Response Relationship, Drug; Enoximone - pharmacology; Fluorescent Dyes; In Vitro Techniques; Myocardial Contraction - drug effects; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Nifedipine - analogs & derivatives; Nifedipine - pharmacology; Phosphodiesterase Inhibitors - pharmacology; Xanthenes
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.104.075895

Historically, inhibitors of type III phosphodiesterases (PDE-III) have been effective inotropes in mammalian myocardium, but their clinical utility has been limited by adverse events, including arrhythmias that are considered to be due to Ca 2+ overload. ATI22-107 [2-(2-{2-[2-chloro-4-(6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-phenoxy]-acetylamino}-ethoxymethyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid dimethyl ester)], a novel, dual pharmacophore compound, was designed to simultaneously inhibit the cardiac phosphodiesterase (PDE-III) and produce inotropic effects, whereas inhibiting the L-type calcium channel (LTCC) was designed to minimize increases in diastolic Ca 2+ . We compared the effects of ATI22-107 and enoximone, a pure PDE-III inhibitor, on the Fluo-3 calcium transient in normal feline ventricular myocytes and trabeculae. Enoximone-induced dose-dependent increases in peak [Ca 2+ ] i , diastolic [Ca 2+ ] i , T50, and T75. ATI22-107 demonstrated similar dose-dependent increases in peak [Ca 2+ ] i at 300 nM and 1.0 μM doses, with no further increases at higher doses. Throughout the dosing range, ATI22-107 induced much smaller, if any, increases in diastolic [Ca 2+ ] i , T 25 , and T 75 . Current measurement of LTCC via patch-clamp techniques revealed dose-dependent decreases in LTCC current with an increasing dose of ATI22-107, thereby validating the dual functionality of the drug that has been proposed in this study. Studies in isolated trabeculae demonstrated that enoximone-induced a dose-dependent augmentation of the entire force-frequency relation in normal myocardium, whereas augmentation of contractility was only observed at lower stimulation frequencies with ATI22-107. These results demonstrate the effects of the LTCC-antagonizing moiety of ATI22-107 and suggest that the novel simultaneous combination of PDE-III and LTCC inhibition by one molecule may produce a favorable profile of limited inotropy without detrimental effects of increased diastolic [Ca 2+ ] i .