Syntheses, Calcium Channel Agonist-Antagonist Modulation Activities, and Voltage-Clamp Studies of Isopropyl 1,4-Dihydro-2,6-dimethyl-3-nitro- 4-pyridinylpyridine-5-carboxylate Racemates and Enantiomers

Abstract

A novel group of racemic isopropyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-pyridinylpyridine-5-carboxylate isomers [(+/-)-12-14] were prepared using a modified Hantzsch reaction that involved the condensation of nitroacetone with isopropyl 3-aminocrotonate and 2-, 3-, or 4-pyridinecarboxaldehyde. Determination of their in vitro calcium channel-modulating activities using guinea pig ileum longitudinal smooth muscle (GPILSM) and guinea pig left atrium (GPLA) assays showed that the 2-pyridinyl isomer (+/-)-12 acted as a dual cardioselective calcium channel agonist (GPLA)/smooth muscle selective calcium channel antagonist (GPILSM). In contrast, the 3-pyridinyl [(+/-)-13] and 4-pyridinyl [(+/-)-14] isomers acted as calcium channel agonists on both GPLA and GPILSM. The agonist effect exhibited by (+/-)-12 on GPLA was inhibited by nifedipine and partially reversed by addition of extracellular Ca2+. In anesthetized rabbits, the 4-pyridinyl isomer (+/-)-14 exhibited a hypertensive effect that was qualitatively similar to that exhibited by the nonselective agonist Bay K 8644 and the 3-pyridinyl isomer (+/)-13, whereas the 2-pyridinyl isomer (+/-)-12 induced a hypotensive effect similar to that of the calcium channel antagonist nifedipine. Similar results were obtained in a spontaneously hypertensive rat model. In vitro studies showed that the (+)-2-pyridinyl enantiomer (+)-12A exhibited agonist activity on both GPILSM and GPLA, but that the (-)-2-pyridinyl enantiomer (-)-12B exhibited agonist activity on GPLA and antagonist activity on GPILSM. Whole-cell voltage-clamp studies using isolated guinea pig ventricular myocytes indicated that (-)-12B inhibited the calcium current (ICa), that (+)-12A increased slightly ICa, and that (+/-)-12 inhibited ICa but the latter inhibition was less than that for (-)-12B. (-)-12B effectively inhibited ICa at all membrane potentials examined (-40-50 mV), whereas (+)-12A exhibited a weak agonist effect near the peak of the I-V curve. The 2-pyridinyl isomers (enantiomers) 12 represent a novel type of 1,4-dihydropyridine calcium channel modulator that could provide a potentially new approach to drug discovery targeted toward the treatment of congestive heart failure and probes to study the structure-function relationships of calcium channels.

Design and syntheses of 4-[3-(1-methoxycarbonyl-1,6-dihydropyridyl)]- and 4-[3-(1-methoxycarbonyl-4-substituted-1,4-dihydropyridyl)]- derivatives of alkyl 1,4-dihydro-2,6-dimethyl-3-nitro-5-pyridine-carboxylates with calcium channel modulating activities

“…6,8 The objective of this study was to determine whether elaboration of the planar 4-(3-pyridyl) substituent of 2b to a as indicated in Table 1]. Although compounds 8 and 14-18 were less potent calcium channel agonist positive inotropes on heart than the reference drug Bay K 8644, both classes of compounds retained positive cardiac inotropic acitivity (see Table 1 …”

“…[4][5] Recently, we discovered a novel third generation class of isomeric isopropyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(pyridyl)-5-pyridinecarboxylates 2a-c with different CC modulation activities. 6 The 2-pyridyl One of the most widely used methods to prepare 1,4-DHPs involves the addition of a nucleophile to activated N-alkyl-or N-acylpyridinium salts. [10][11][12] The 1,4-versus 1,2-regioselectivity of this reaction is dependent upon the activating N-substituent, the nucleophile, and the nature and position of pyridinium substituents.…”

“…In this regard, reaction 15 , 17 of the ketal 9 with MeOCOCl and a Grignard reagent in the presence of Me 2 S and CuI afforded the 1,4-DHP ketal derivative 10, which on deprotection using 5% HCl, yielded the target 1-methoxycarbonyl-4-substituted-1,4-dihydropyridyl-3-carboxaldehydes 11a-c as illustrated in Scheme 2. The subsequent condensation of an aldehyde 11 with the alkyl 3-aminocrotonate 12 and nitroacetone 13, using a modified Hantzsch reaction, 6 afforded the respective alkyl 1,4-dihydro-2,6-dimethyl-3-nitro-4- …”

A One-pot Multi-component Synthesis of Dihydropyrimidinone/Thione and Dihydropyridine Derivatives via Biginelli and Hantzsch Condensations using t-BuOK as a Catalyst Under Solvent-free Conditions

“…DHP drugs, namely nifedipine, nicardipine and amlodipine, are cardiovascular agents for the treatment of hypertension [2]. A number of DHP calcium antagonists have been introduced as potential drugs for the treatment of congestive heart failure [3]. In addition, dihydropyridines find applications in stereo specific hydrogen transfer reduction of phenylglyoxylic and pyruvic acid to biomimetic models of lactase dehydrogenase [4].…”

Tetrabutylammonium Hexatungstate [Tba]2[w6o19]: A Novel Heterogeneous Catalyst for One-Pot Synthesis of Hantzsch 1,4-Dihydropyridines in Solvent-Free

“…Dihydropyridine drugs, namely nifedipine, nicardipine and amlodipine, are cardiovascular agents for the treatment of hypertension 2,3 . A number of dihydropyridine derivatives are employed as potential drug candidates for the treatment of congestive heart failure 4 . In human body the main metabolic route of dihydropyridine drugs involve their oxidation to pyridines catalyzed by cytochrome-450 in liver 5 .…”