Syntheses, calcium channel agonist‐antagonist modulation effects, and nitric oxide release studies of [3‐(Benzenesulfonyl)furoxan‐4‐yloxy]alkyl 1,4‐Dihydro‐2,6‐dimethyl‐5‐nitro‐4‐(2‐trifluoromethylphenyl, benzofurazan‐4‐yl, 2‐, 3‐, or 4‐pyridyl)‐3‐pyridinecarboxylates

Abstract

A group of racemic 1,4-dihydro-2,6-dimethyl-5-nitro-3-pyridinecarboxylates possessing either a C-4 2-trifluoromethylphenyl (22-24), benzofurazan-4-yl (42-44), 2-pyridyl (45-47), 3-pyridyl (48-50), or 4-pyridyl (51-53), substituent in conjunction with a nitric oxide donor C-3 ester [3-(benzenesulfonyl)furoxan-4-yloxy]alkyl substituent were synthesized using modified Hantzsch reactions. Compounds 45-53 having a C-4 2-, 3-, or 4-pyridyl substituent exhibited more potent in vitro calcium channel antagonist activity (IC 50 's in the 0.46 to 5.23 mM range) on guinea pig ileum longitudinal smooth muscle (GPILSM) than related analogs having a C-4 2-trilfuoromethylphenyl (22-24) or benzofurazan-4-yl (42, 44) substituent (IC 50 Z 29.91 mM). The point of attachment of the pyridyl ring (2-, 3-, or 4-), and the length of the C-3 ester alkyl spacer [-CH 2 (CH 2 )n, n ¼ 1-3], were not determinants of smooth muscle calcium channel antagonist activity. Replacement of the C-3 ester methyl substituent of Bay K 8644, or the ester isopropyl substituent of the 4-(pyridyl) isomers 4a-c by a [3-(benzensulfonyl)furoxan-4-yloxy]alkyl moiety retained the desired calcium channel agonist (positive inotropic) effect on guinea pig left atrium (GPLA). Compounds having C-4 3-pyridyl (48-50), or 4-pyridyl (51-53), substituents were the most potent cardiac positive inotropes (EC 50 's in the 3.02 to 19.74 mM range) relative to the reference drug Bay K 8644 IC 50 ¼ 0.77 mM). The % nitric oxide released in vitro in the presence of L-cysteine for this group of compounds was higher (36-74% range) than for the reference drug glycerol trinitrate (20%). A quantitative structure-activity analysis showed an inverse correlation between a molecular weight (MW) descriptor and % nitric oxide released. Model hybrid (calcium channel modulation, nitric oxide donor) compounds that show dual cardioselective agonist (positive inotropic)/smooth muscle selective antagonist activities constitute a novel type of 1,4-dihydropyridine calcium channel modulator that provides a potential drug design concept targeted toward the treatment of congestive heart failure, and is a useful probe to study the structure-function relationship of calcium channels. Drug. Dev. Res. 56:1-16, 2002.

NO donors: Focus on furoxan derivatives

“…All these NO donor hybrids were reviewed [2,17]. More recently, NO donor furoxans were also joined to 1,4-dihydropyridine Ca 2+ -channel activators [18], as well as to the REC15/2739, a uroselective α 1 -antagonist [19], and to the rabeprazole, a potent inhibitor of H + /K + -ATPase enzyme [20]. One of the problems that must be addressed when working with hybrid drugs is their balance.…”

Syntheses, calcium channel modulation effects, and nitric oxide release studies of O2‐alkyl‐1‐(pyrrolidin‐1‐yl) diazen‐1‐ium‐1,2‐diolate 4‐aryl(heteroaryl)‐1,4‐dihydro‐2,6‐dimethyl‐3‐nitropyridine‐5‐carboxylates

“…Silica gel column chromatography was performed using silica gel (70-230 mesh) purchased from Silicycle (Quebec, Canada). Sodium 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (6) [Saavedra et al, 1997], O 2 -chloromethyl-1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (7) [Tang et al, 2001], and the 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl, 2-, 3-, or 4-pyridyl, benzofurazan-4-yl)pyridine-5-carboxylates (11-15) [Vo et al, 2002] were prepared according to procedures reported in the literature. All other reagents were purchased from Aldrich Chemical (Milwaukee, WI).…”

“…e No calcium channel agonist response (positive inotropic effect) on heart was observed at the highest test compound concentration used (44.66 mM). f Data for racemates are taken from the literature [Vo et al, 2002].…”

New 1,4-Dihydropyridines Endowed with NO-Donor and Calcium Channel Agonist Properties

“…Hybrid structures in which 1,4-dihydropyridines able to activate L-type Ca 2+ channels are connected with suitable NO-donor moieties could represent a new interesting class of positive inotropic agents, devoid of vasoconstrictor properties. Two examples of this approach were recently reported in the literature. , On these bases, we designed new 1,4-dihydropyridines formally obtained by substitution of appropriately substituted NO-donor furoxan substructures for the CF 3 group in Bay K 8644 (derivatives 8 , 9 , 10 ). We herein describe the syntheses of these products and the action of their racemic mixtures on L-type Ca 2+ channels expressed by rat insulinoma cell line (RINm5F cells).…”