Calcium Channel Antagonist Activity Research Articles

Synthesis, QSAR and Calcium Channel Antagonist Activity of New 1,4‐Dihydropyridine Derivatives Containing 1‐Methyl‐4,5‐dichloroimidazolyl Substituents

A group of dialkyl and diarylester analogues of nifedipine, in which the ortho-nitrophenyl group at position 4 was replaced by a 1-methyl-4,5-dichloroimidazolyl substituent, were synthesized and evaluated as calcium-channel antagonists using the high K(+)concentration of guinea-pig ileum longitudinal smooth muscle. The structure of all compounds was confirmed by IR,(1)H-NMR, and mass spectra. The calcium-channel antagonist activity of compounds 10a-f demonstrated that compound 10b was the most active and 10f the least active one. With unsymmetrical diesters 12a-k, the most active compound was the ethyl, phenethyl derivative. Structural parameters on the calcium-channel antagonist activity were evaluated by QSAR analysis and a linear correlation was found between the -log IC(50) values of these compounds and their constitutional and topological properties.

Modeling calcium channel antagonistic activity of dihydropyridine derivatives using QTMS indices analyzed by GA-PLS and PC-GA-PLS

The usefulness of a novel type of electronic descriptors called quantum topological molecular similarity (QTMS) indices for describing the quantitative effects of molecular electronic environments on the antagonistic activity of some dihydropyridine (DHP) derivatives has been evaluated. QTMS theory produces a matrix of descriptors, including bond (or structure) information in one dimension and electronic effects in another dimension, for each molecule. Some different modeling tools such as multiple linear regression (MLR), principal component analysis (PCA), partial least squares (PLS) and genetic algorithms (GA) were employed to find some appropriate models for noted biological activity. GA was used in order to select the proper variables and also PCA was used for data compression. Then modeling was performed by MLR and PLS. The model performances were accessed by both cross-validation and external prediction set. The results showed that the proposed models could explain above 90% of variances in the biological activity. The significant effects of chemical bonds on the antagonistic activity were identified by calculating variable important in projection (VIP). It was obtained that those belonging to the substituted 4-phenyl ring represent high influence on the biological activity which, confirms their importance in mechanism of action of DHP derivatives.

Molecular modeling and QSAR analysis of some 4,5-dichloroimidazolyl-1,4-DHP-based calcium channel blockers

The effects of the structural features of some 4,5-dichloroimidazolyl-1,4-dihydropyridine on their calcium channel antagonist activity have been studied using molecular modeling and quantitative structure activity-relationship analysis. Both symmetrical and asymmetrical dihydropyridine derivatives were used. AM1 semi-empirical quantum chemical calculation was used to find the optimum 3-D geometry of the molecules. Four different sets of descriptors, including chemical, topological, quantum chemical and substituent constant, were then calculated for each molecule. For each set of descriptors, the best multilinear QSAR equations were obtained by the stepwise variable selection method using leave-one-out cross-validation as selection criterion. Separate QSAR models were first obtained for symmetrical and asymmetrical derivatives, after which a general model was proposed for the entire set of molecules. This model has root mean square error of 0.45 and reproduces more than 82% of the variances in the calcium channel antagonist activity data. The sum of the negative charges, the energy of the highest occupied molecular orbital, molecular volume and the least negative charge were identified as the most significant descriptors.

Synthesis of alkyl 6‐methyl‐4‐(2‐pyridyl)‐1,2,3,4‐tetrahydro‐2H‐pyrimidine‐2‐one‐5‐carboxylates for evaluation as calcium channel antagonists

Abstractmagnified imageThe Bigenelli acid catalyzed condensation of 2‐pyridylcarboxaldehyde (1), urea (2) and an alkyl acetoacetate (3) afforded the respective alkyl (Me, Et, i‐Pr, i‐Bu, t‐Bu) 6‐methyl‐4‐(2‐pyridyl)‐1,2,3,4‐tetrahydro‐2H‐pyrimidine‐2‐one‐5‐carboxylates (4a‐e). The most potent calcium channel antagonist ethyl 6‐methyl‐4‐(2‐pyridyl)‐1,2,3,4‐tetrahydro‐2H‐pyrimidine‐2‐one‐5‐carboxylate (4b, IC50 = 1.67 × 10−5 M) wasa much weaker calcium channel antagonist than the reference drug nifedipine (Adalat®, IC50 = 1.40 × 10−8 M) on guinea pig ileal longitudinal smooth muscle (GPILSM). The alkyl 6‐methyl‐4‐(2‐pyridyl)‐1,2,3,4‐tetrahydro‐2H‐pyrimidine‐2‐one‐5‐carboxylates did not show any inotropic effect on heart since no increase, or decrease, in the contractile force of guinea pig left atrium was observed. These structure activity studies show that the alkyl 6‐methyl‐4‐(2‐pyridyl)‐1,2,3,4‐tetrahydro‐2H‐pyrimidine‐2‐one‐5‐carboxylates (4a‐e) are partial bioisosteres of nifedipine with respect to calcium channel antagonist activity on guinea pig ileal longitudinal smooth muscle (GPILSM).

Synthesis and calcium channel antagonist activities of new derivatives of dialkyl 1,4-dihydro-2,6-dimethyl-4-(5-phenylisoxazol-3-yl)pyridine-3,5-dicarboxylates

The new analogues of nifedipine, in which 2-nitrophenyl group at position 4 is replaced by phenylisoxazolyl substituent, were synthesized. The symmetrical dialkyl 1,4-dihydro-2,6-dimethyl-4-(5-phenylisoxazol-3-yl)pyridine-3,5-dicarboxylates were prepared by classical Hantzsch condensation, and the asymmetrical analogues were synthesized using a procedure reported by Dagnino that involved the condensation of alkyl acetoacetate with alkyl 3-aminocrotonate and 5-phenylisoxazole-3-carboxaldehyde. The structure of all compounds was confirmed by IR, 1H NMR and Mass spectra. In vitro calcium channel antagonist activities were evaluated as calcium channel antagonists using the high K+ concentration of guinea-pig ileum longitudinal smooth muscle (GPILSM) assay. These compounds exhibited moderate calcium antagonist activity (IC50 = 10−7 to 10− 5 M range) relative to the reference drug nifedipine (IC50 = 1.10 ± 0.40 × 10−8 M).

The Synthesis and Characterization of New Asymmetrical Dihydropyridine Derivatives Containing a 2,4-Dichloro-5-Thiazolyl Substituent

Dihydropyridines (DHP) having a heterocyclic aryl substituent at position-4 are calcium channel antagonists. In this report a new group of DHP derivatives with different esters at the C 3 and C 5 position (asymmetrical diesters) containing 2,4-dichloro-5-thiazolyl at position-4 were synthesized by a condensation reaction of alkyl, cycloalkyl, and aryl acetoacetate in the presence of ammonium acetate in a new shorter pathway. The structure of all compounds was confirmed by IR, 1 H NMR, and mass spectrometry. The calcium channel antagonist activity of compounds 6a–6f demonstrated that the compound 6a was the most active compound.

Design, Synthesis, and Calcium Channel Antagonist Activity of New 1,4‐Dihydropyridines Containing 4‐(5)‐Chloro‐2‐ethyl‐5‐(4)‐imidazolyl Substituent.

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Ranolazine for the Treatment of Chronic Angina and Potential Use in Other Cardiovascular Conditions

Chronic angina, a condition that impairs quality of life and is associated with decreased life expectancy, affects &6.4 million Americans.1 Current therapies that reduce angina frequency and nitrate consumption and increase the threshold at which demand-induced myocardial ischemic symptoms become evident include drugs (nitrates, β-blockers, calcium antagonists), exercise conditioning, enhanced external counterpulsation, and coronary revascularization.1–3 Several new investigational drugs are being tested for the treatment of chronic angina.4–9 This review will focus on sustained-release ranolazine, a drug that reduces angina symptoms, with a mechanism of action different from that of currently available pharmacological therapies.8–29 Ranolazine was approved on January 27, 2006, in the United States for use in patients with chronic angina who continue to be symptomatic on β-blockers, calcium antagonists, or nitrates. Ranolazine ([(+) N -(2,6-dimethylphenyl)-4(2-hydroxy-3-(2-methoxyphenoxy)-propyl)-1-piperazine acetamide dihydrochloride]) is an active piperazine derivative that was patented in 1986 and is available in an oral and intravenous form (Figure 1). The immediate-release ranolazine (not in current use) had an average terminal elimination half-life ranging from 1.4 to 1.9 hours and a 10-fold peak/trough difference with dosing of 240 to 400 mg 3 times per day.19 Early studies with immediate-release ranolazine provided evidence of antiischemic/antianginal properties in patients with chronic angina without clinically significant changes in heart rate or blood pressure and are reviewed elsewhere.20–24 Unless otherwise stated, the remainder of this review refers to sustained-release ranolazine. Figure 1. Chemical structure and metabolism of ranolazine. Reprinted with permission from J Clin Pharmacol . 2005;45:422–433.17 Ranolazine (Ranexa; CV Therapeutics Inc, Palo Alto, Calif) is manufactured in a sustained-release form that has a prolonged absorption phase with maximal plasma concentrations (Cmax) typically seen 4 to 6 hours after administration. The average terminal elimination half-life is &7 hours after multiple dosing to steady state, and the …

Design, Synthesis, and Calcium Channel Antagonist Activity of New 1,4‐Dihydropyridines Containing 4‐(5)‐Chloro‐2‐ethyl‐5‐(4)‐imidazolyl Substituent

A series of dialkyl, dicycloalkyl, and diaryl ester analogues of nifedipine, in which the ortho-nitro phenyl group at position 4 is replaced by the 4-(5)-chloro-2-ethyl-5-(4)-imidazolyl substituent, were synthesized and evaluated as calcium channel antagonists using the high K+ contraction of guinea pig ileal longitudinal smooth muscle. The results for the symmetrical ester series showed that increasing the length of the chain in C3- and C5-ester substituents increased the activity and the most active compound was the diphenylethyl ester derivative, so it was more active than the reference drug nifedipine. In unsymmetrical diester series, when R1 is methyl or ethyl, increasing lipophilic properties in the R substituent, increased the activity. The most active compounds were methyl/phenethyl and ethyl/phenethyl ester derivatives, being slightly more active than nifedipine.

Design and synthesis of alkyl 7,7-dihalo-3-methyl-5-(nitrophenyl)-2-azabicyclo[4.1.0]hept-3-ene-4-carboxylates with calcium channel antagonist activity

A group of alkyl 7,7-dihalo-3-methyl-5-(2- or 3-nitrophenyl)-2-azabicyclo[4.1.0]hept-3-ene-4-carboxylates were prepared by reaction of dihalocarbenes (:CX 2, X = Br, Cl) with alkyl 2-methyl-4-(2- or 3-nitrophenyl)-1,4-dihydropyridine-3-carboxylates. In vitro calcium channel antagonist activities were determined using a guinea pig ileum longitudinal smooth muscle assay. The title compounds exhibited weaker CC antagonist activity (10 −5 to 10 −7 M range) than the reference drug nifedipine (1.4 × 10 −8 M). Structure–activity relationships showed that the position ( ortho or meta) of the nitro-substituent on the C-5 phenyl ring, the size (van der Waal’s radius for Br and Cl are 1.95 and 1.80 Å, respectively) and/or electronegativity (Cl > Br) of the C-7 geminal halogen atoms do not appear to have a significant effect on CC antagonist activity. In contrast, the effect of the alkyl ester substituent was more pronounced where compounds having a Me or Et alkyl ester group showed superior potency (IC 50 in the 10 −7 M range) relative to the reference drug nifedipine (IC 50 = 1.40 × 10 −8 M). Replacement of a 2-methyl-3-methoxycarbonylvinyl moiety present in nifedipine by a bioisosteric geminal-dihalocyclopropyl moiety provided a novel class of calcium channel antagonists that do not exhibit any inotropic effect on guinea pig atria.

Hantzsch 1,4-dihydropyridines containing a diazen-1-ium-1,2-diolate nitric oxide donor moiety to study calcium channel antagonist structure–activity relationships and nitric oxide release

A group of racemic 3-isopropyl 5-[(2-piperazin-1-yl)ethyl] 1,4-dihydro-2,6-dimethyl-4-(pyridyl)-3,5-pyridinedicarboxylates ( 12a– c), 3-isopropyl 5-{2-[4-nitrosopiperazinyl]ethyl} 1,4-dihydro-2,6-dimethyl-4-(pyridyl)-3,5-pyridinedicarboxylates ( 14a– c) and 3-isopropyl 5-{2-[( O 2-acetoxymethyldiazen-1-ium-1,2-diolate)( N, N-dialkylamino or 4-piperazin-1-yl)]ethyl} 1,4-dihydro-2,6-dimethyl-4-(pyridyl)-3,5-pyridinedicarboxylates ( 22– 30) were prepared using modified Hantzsch reactions. This group of compounds ( 12a– c, 14a– c, and 22– 30) exhibited less potent calcium channel antagonist activity (IC 50 = 0.11 to 3.35 μM range) than the reference drug nifedipine (IC 50 = 0.01 μM). The point of attachment of the isomeric C-4 substituent was a determinant of calcium channel antagonist activity providing the potency profile 2-pyridyl ⩾ 3-pyridyl ⩾ 4-pyridyl. The N-nitrosopiperazinyl compounds ( 14a– c) did not release nitric oxide. The prodrugs 22– 30 that have a C-5 2-[( O 2-acetoxymethyldiazen-1-ium-1,2-diolate)( N, N-dialkylamino or 4-piperazin-1-yl)]ethyl ester substituent, upon incubation with guinea pig serum, undergo consecutive cleavage of the O 2-acetoxymethyl moiety to give a nitric oxide donor diazenium-1-ium-1,2-diolate species that subsequently releases nitric oxide. The extent of nitric oxide released from the diazen-1-ium-1,2-diolate group is dependent upon the nature of the amino functionality attached directly to the diazen-1-ium N-1 position where the nitric oxide release profile is 1,4-piperazinyl > N-Et > N-( n-Bu) ≫ N-Me upon exposure to guinea pig serum esterase(s). The results from this study suggest this class of hybrid calcium channel antagonist/nitric oxide donor prodrugs should release the vasodilator nitric oxide in vivo, preferentially in the vascular endothelium, to enhance the smooth muscle calcium channel antagonist effect to produce a combined synergistic antihypertensive effect.

Synthesis and Calcium Channel Antagonist Activity of New 1,4‐Dihydropyridine Derivatives Containing Lipophilic 4‐Imidazolyl Substituents.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of Dialkyl 1,4‐Dihydro‐2,6‐dimethylpyridine‐3,5‐dicarboxylates and Alkyl 1,4‐Dihydro‐2,6‐dimethyl‐3‐nitropyridine‐5‐carboxylates Possessing a C‐4 2,4‐Dioxo‐1,2,3,4‐tetrahydropyrimidin‐5‐yl (Uracil) Substituent to Determine Calcium Channel Modulation Structure—Activity Relationships.

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Synthesis and biological evaluation of 1,4-dihydropyridine calcium channel modulators having a diazen-1-ium-1,2-diolate nitric oxide donor moiety for the potential treatment of congestive heart failure

A group of racemic 4-aryl(heteroaryl)-1,4-dihydro-2,6-dimethyl-3-nitropyridines possessing nitric oxide donor O 2-acetoxymethyl-1-( N-ethyl- N-methylamino, or 4-ethylpiperazin-1-yl)diazen-1-ium-1,2-diolate, C-5 ester substituents were synthesized by coupling the respective 4-aryl(heteroaryl)-1,4-dihydro-2,6-dimethyl-3-nitropyridine-5-carboxylic acids with either O 2-acetoxymethyl-1-[ N-(2-methylsulfonyloxyethyl)- N-methylamino]diazen-1-ium-1,2-diolate, or O 2-acetoxymethyl-1-[4-(2-methylsulfonyloxyethyl)piperazin-1-yl]diazen-1-ium-1,2-diolate. Compounds having a C-4 2-pyridyl, 4-pyridyl, 2-trifluoromethylphenyl, or benzofurazan-4-yl substituent exhibited more potent smooth muscle calcium channel antagonist activity (IC 50's in the 0.37–1.09 μM range) than related analogs having a C-4 3-pyridyl substituent (IC 50's=3.03–9.14 μM range) relative to the reference drug nifedipine (IC 50=9.13 nM). The point of attachment of C-4 isomeric pyridyl substituents was a determinant of smooth muscle calcium channel antagonist activity where the relative potency profile was 4-pyridyl>2-pyridyl>3-pyridyl. Replacement of the C-5 methyl ester substituent of methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)pyridine-5-carboxylate (Bay K 8644) by an O 2-acetoxymethyl-1-( N-ethyl- N-methylamino)diazen-1-ium-1,2-diolate, or O 2-acetoxymethyl-1-(4-ethylpiperazin-1-yl)diazen-1-ium-1,2-diolate, C-5 ester substituent provided compounds, which exhibited a lower, yet respectable, cardiac positive inotropic effect (IC 50's=4.82 and 4.05 μM, respectively) relative to the reference drug Bay K 8644 (IC 50=0.30 μM). All compounds released nitric oxide upon incubation with either phosphate buffer at pH 7, or porcine liver esterase. However, the percentage nitric oxide released was up to 3-fold higher (76%) when these O 2-acetoxymethyl-1-(alkylamino)diazen-1-ium-1,2-diolates were incubated with guinea pig serum. These results suggest that NO would be released in vivo, upon cleavage by nonspecific serum esterases, preferentially in the vascular endothelium where it may enhance smooth muscle calcium channel antagonist activity.

Design and synthesis of methyl 2-methyl-7,7-dihalo-5-phenyl-2-azabicyclo64.1.09hept-3-ene-4-carboxylates with calcium channel antagonist activity

Graphic A group of methyl 2-methyl-7,7-dihalo-5-(substituted-phenyl)-2-azabicyclo[4.1.0]hept-3-ene-4-carboxylates were prepared by reaction of dihalocarbenes (:CX 2 , X = Br, Cl) with methyl 1-methyl-4-(substituted-phenyl)-1,4-dihydropyridine-3-carboxylates. In vitro calcium channel antagonist activities were determined using a guinea pig ileum longitudinal smooth muscle assay. The title compounds exhibited weaker CC antagonist activity (10 −5 –10 −6 M range) than the reference drug nifedipine (1.4 × 10 −8 M). Structure–activity relationship studies showed that the position of a nitro substituent on the C-5 phenyl ring where the relative potency order was ortho > meta > para , and the size and/or electronegativity of the C-7 geminal-dihalo substituents (Br > Cl), were determinants of calcium channel antagonist activity. This class of compounds did not exhibit any inotropic effect on guinea pig left atria. A dihalocyclopropyl moiety is a potential bioisostere for the 2-methyl-3-methoxycarbonylvinyl moiety present in the calcium channel antagonist nifedipine.

Design and synthesis of methyl 2-methyl-7,7-dihalo-5-phenyl-2-azabicyclo[4.1.0]hept-3-ene-4-carboxylates with calcium channel antagonist activity

A group of methyl 2-methyl-7,7-dihalo-5-(substituted-phenyl)-2-azabicyclo[4.1.0]hept-3-ene-4-carboxylates were prepared by reaction of dihalocarbenes (:CX 2, X = Br, Cl) with methyl 1-methyl-4-(substituted-phenyl)-1,4-dihydropyridine-3-carboxylates. In vitro calcium channel antagonist activities were determined using a guinea pig ileum longitudinal smooth muscle assay. The title compounds exhibited weaker CC antagonist activity (10 −5–10 −6 M range) than the reference drug nifedipine (1.4 × 10 −8 M). Structure–activity relationship studies showed that the position of a nitro substituent on the C-5 phenyl ring where the relative potency order was ortho > meta > para, and the size and/or electronegativity of the C-7 geminal-dihalo substituents (Br > Cl), were determinants of calcium channel antagonist activity. This class of compounds did not exhibit any inotropic effect on guinea pig left atria. A dihalocyclopropyl moiety is a potential bioisostere for the 2-methyl-3-methoxycarbonylvinyl moiety present in the calcium channel antagonist nifedipine.

Synthesis of dialkyl 1,4‐dihydro‐2,6‐dimethylpyridine‐3,5‐dicarboxylates and alkyl 1,4‐dihydro‐2,6‐dimethyl‐3‐nitropyridine‐5‐carboxylates possessing a c‐4 2,4‐dioxo‐1,2,3,4‐tetrahydropyrimidin‐5‐yl (uracil) substituent to determine calcium channel modulation structure‐activity relationships

AbstractThe Hantzsch condensation of 5‐formyluracil (1) with methyl, isopropyl or isobutyl acetoacetate (2a‐c) in the presence of ammonium hydroxide afforded the respective dialkyl 1,4‐dihydro‐2,6‐dimethyl‐4‐(2,4‐dloxo‐1,2,3,4,‐tetrahydropyrimidin‐5‐yl)pyridine‐3,5‐dicarboxylate (3a‐c). A group of alkyl 1,4‐dihydro‐2,6‐dimethyl‐3‐nitro‐4‐(2,4‐dioxo‐1,2,3,4‐tetrahydropyrimidin‐5‐yl)pyridine‐5‐carboxylates (6a‐c) were also prepared using a modified Hantzsch reaction that involved the condensation of 5‐formyluracil with nitroacetone and either methyl, isopropyl or isobutyl 3‐aminocrotonate (5a‐c). A C‐4 2,4‐dioxo‐1,2,3,4‐tetrahydropyrimidin‐5‐yl substituent is not a suitable bioisostere for the traditional C‐4 aryl or heteroaryl substituents present in 1,4‐dihydropyridine calcium channel modulators since diisopropyl 1,4‐dihydro‐2,6‐dimemyl‐4‐(2,4‐dioxo‐1,2,3,4‐tetrahydropyrimidin‐5‐yl)pyridine‐3,5‐dicarboxylate (3b) and isobutyl 1,4‐dihydro‐2,6‐dimethyl‐3‐nitro‐4‐(2,4‐dloxo‐1,2,3,4‐tetrahydropyrimidin‐5‐yl)pyridine‐5‐carboxylate (6c) did not exhibit any in vitro calcium channel antagonist activity using a guinea pig smooth muscle calcium channel antagonist assay, or a guinea pig left atrium calcium channel agonist (positive inotropic) assay.

Lipophilic 4-imidazoly-1,4-dihydropyridines: synthesis, calcium channel antagonist activity and protection against pentylenetetrazole-induced seizure

A group of alkyl, cycloalkyl and aryl ester analogs of nifedipine, in which the o-nitrophenyl group at position 4 is replaced by a 2-phenyl-4(5)-imidazolyl substituent, were synthesized and evaluated as calcium channel antagonist using the high K + contraction of guinea-pig ileal longitudinal smooth muscle, and the activity of 5a–d, 8b and 8f against pentylenetetrazole (PTZ)-induced seizure was assessed. The results for symmetrical esters showed that lengthening of the methylene chain in C 3 and C 5 ester substituents increased activity. When increasing of the length is accompanied by increasing the hindrance, the activity decreased. In contrast to symmetrical derivatives, comparison of the activities of asymmetrical esters showed that increasing the length of the methylene chain was accompanied by a decrease in their activity. The results demonstrate that 8a was more active, and 5c and 8f were similar in effect to that of the reference drug nifedipine. The time-course of anticonvulsant effect on PTZ-induced seizure threshold of said compounds was assessed and showed that increasing the lipophilicity decreases the time needed for maximum effect. Mice treated with intraperitoneal injection of 25 mg/kg of these derivatives all exhibited increase seizure threshold as compared with control.

Syntheses, calcium channel agonist-antagonist modulation activities, and nitric oxide release studies of nitrooxyalkyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2,1,3-benzoxadiazol-4-yl)pyridine-5-carboxylate racemates, enantiomers, and diastereomers.

A novel group of hybrid calcium channel (CC) modulators was prepared where the isopropyl ester moiety of isopropyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2,1,3-benzoxadiazol-4-yl)pyridine-5-carboxylate (PN 202-791) was replaced by a variety of nitric oxide (*NO) donor nitrooxyalkyl ester substituents. Enantiomers, or diastereomers, having the (R)-configuration at the C-4 position of the 1,4-dihydropyridine ring (1,4-DHP) exhibited more potent in vitro CC antagonist activity on guinea pig ileum longitudinal smooth muscle (GPILSM) than compounds having the (4S)-configuration. None of the nitrooxyalkyl compounds exhibited a contraindicated CC agonist effect on GPILSM that would cause smooth muscle contraction. Structure-activity studies showed the enantiomers having the (S)-configuration at the C-4 position of the 1,4-DHP ring or diastereomers having the a (4S)-configuration at the C-4 position of the 1,4-DHP ring in conjunction with a (1R-)-1-methyl-2-nitrooxyethyl ester substituent exhibited the most potent cardiac CC agonist (positive inotropic) activity on guinea pig left atrium (GPLA). This class of compounds releases *NO in vitro that is enhanced by the presence of a thiol such as N-acetylcysteamine. The novel *NO donor (-)-(S,R)-1-methyl-2-nitrooxyethyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2,1,3-benzoxadiazol-4-yl)pyridine-5-carboxylate [(-)-(S,R)-38], which acts as a dual cardioselective calcium channel agonist (GPLA)/smooth muscle selective calciumchannel antagonist (GPILSM), is a useful lead compound for drug discovery targeted to the treatment of congestive heart failure, and it provides a useful research probe to study the structure-function relationship of calcium channels.

Quantum Chemical‐QSAR Study of Some Newly Synthesized 1,4‐Dihydropyridine Calcium Channel Blockers

AbstractA QSAR analysis was conducted on the calcium channel antagonist activity of 72 C‐3 and C‐5 ester‐substituted 4‐(nitro imidazolyl) 1,4‐dihydropyridine derivatives. Quantum chemical descriptors including atomic charges, electrostatic potentials, HOMO and LUMO energies, electronegativity, electrophilicity, hardness and softness indices were calculated using ab‐initio method with gaussian98 at RHF/6‐21G level. Multiple linear regression was used to model the relationships between molecular descriptors and biological activity of molecules using genetic algorithm as variable selection tool (GA‐MLR). A high quality multi‐parametric QSAR model was obtained. The prediction ability of the resulting models was evaluated by the prediction of the activity of the prediction set compounds, which did not contribute to the model building at all. Addition of the physicochemical parameters to the electronic features of the molecules enhanced the prediction ability of the models. Artificial neural network, combined with genetic algorithm for feature selection (GA‐ANN), was also employed to model nonlinear structure‐activity relationships. The results showed that ANN gave more appropriate QSAR models in comparison with those obtained by MLR. The root mean square error of prediction for the best MLR and ANN models, which used 6 descriptors as predictor variables, was equal to 0.60 and 0.21, respectively. Also, the squared correlation coefficient of these models was 0.874 and 0.988, respectively.