Synthesis and Smooth Muscle Calcium Channel Antagonist Effects of Dialkyl 1,4‐Dihydro‐2,6‐dimethyl‐4‐aryl‐3,5‐pyridinedicarboxylates Containing a Nitrooxy or Nitrophenyl Moiety in the 3‐Alkyl Ester Substituent

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A group of racemic nitrooxyalkyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(pyridinyl or 2-trifluoromethylphenyl)-5-pyridinecarboxylates 8a-o were synthesized using modified Hantzsch reactions. In vitro calcium channel antagonist activities, determined using a guinea pig ileum longitudinal smooth muscle (GPILSM) assay, showed that compounds 8a-o exhibited weaker calcium antagonist activity (10 -5 to 10 -7 M range) than the reference drug nifedipine (IC 50 = 1.43 × 10 -8 M). Compounds 8 possessing a C-4 R 1 = 2-pyridyl substituent were always more potent than the approximately equiactive analogs having an R 1 = 3-pyridyl, 4-pyridyl or 2-CF 3 -C 6 H 4 -substituent, within each subgroup of nitrooxyalkyl compounds [R 2 = -(CH 2 ) n ONO 2 (n = 2, 3, 4) or -CH(CH 2 ONO 2 ) 2 ]. Although the length of the R 2 = -(CH 2 ) n ONO 2 substituent (n = 2-4) was not a determinant of smooth muscle calcium antagonist activity when the C-4 R 1 -substituent was 2-pyridyl, when R 1 was a 3-pyridyl, 4-pyridyl, or 2-CF 3 -C 6 H 4 -substituent, the relative potency order with respect to the R 2 = -(CH 2 ) n ONO 2 substituent was n = 3 and 4 > n = 2. Replacement of the isopropyl substituent of the ester moiety of the calcium antagonist (±)-2-pyridyl 3a by a -(CH 2 ) n ONO 2 (n = 2-4) moiety increased calcium antagonist activity on GPILSM by 8-fold. In contrast, replacement of the isopropyl substituent of the ester moiety of the calcium agonists (±)-3-pyridyl 3b, (±)-4-pyridyl 3c or the methyl substituent of the ester moiety of Bay K8644 by a R 2 nitrooxyalkyl substituent resulted in abolition of their calcium agonist effects on GPILSM that is replaced by a smooth muscle calcium antagonist effect. These calcium antagonist data support the concept that incorporation of a nitrooxyalkyl ester substituent constitutes a valuable drug design strategy to enhance Hantzsch 1,4-dihydropyridine calcium antagonist and/or abolish calcium agonist effects on smooth muscle. Replacement of the isopropyl (8bc), or the methyl (8d) group by a -CH 2 CH 2 ONO 2 moiety resulted in retention of the cardiac positive inotropic effect where the relative potency order with respect to the C-4 substituent was 2-CF 3 -C 6 H 6 -(8d) > 3-pyridyl (8b) ≈ 4-pyridyl (8c). Model hybrid (calcium channel modulation, ·NO release) compounds, that exhibit dual cardioselective agonist / smooth muscle selective antagonist activities, represent a novel type of 1,4-dihydropyridine CC modulator that offers a potential approach to drug discovery targeted toward the treatment of congestive heart failure and for use as probes to study the structure-function relationship of calcium channels. Drug Dev. Res. 51:225-232, 2000.

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synthesis and calcium channel modulating effects of modified Hantzsch nitrooxyalkyl 1,4‐dihydro‐2,6‐dimethyl‐3‐nitro‐4‐(pyridinyl or 2‐trifluoromethylphenyl)‐5‐pyridinecarboxylates

Miri

McEwen

Knaus

2000

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“…Accordingly, organic nitrovasodilators that exert their effect in vivo by bypassing the NO-production system in the endothelium to deliver NO directly to muscle cells in the artery has prompted us [Iqbal and Knaus, 1996;Nguyen et al, 2000] and others [Ogawa et al, 1993;Cena et al, 2001] to design hybrid Hantzsch-type 1,4-DHP calcium channel antagonists that have the ability to simultaneously release NO. This hybrid drug design concept was used successfully to eliminate the calcium channel agonist effect of (À)-(S)-Bay K 8644 (1) on smooth muscle.…”

Section: Introductionmentioning

confidence: 99%

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

Nguyen

McEwen

et al. 2002

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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.

“…Accordingly, NO donors that also exhibit antiplatelet and vasodilator activities can be used in either acute or preventative treatment of myocardial ischemia or acute heart failure [Wang et al, 2002]. The discovery that organic nitrovasodilators such as nitroglycerin exhibit their in vivo effect by circumventing the NO-production system in the endothelium to deliver NO directly to arterial muscle cells stimulated studies [Ogawa et al, 1993;Iqbal and Knaus, 1996] to investigate hybrid Hantzsch-type 1,4-DHP CC antagonist /NO donor agents. In an earlier study, we exploited this hybrid drug design technique to effectively abolish the adverse CC agonist effect of (-)-(S)-Bay K 8644 (1) on smooth muscle.…”

Section: Introductionmentioning

confidence: 99%

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

Velázquez

Knaus

2003

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A group of racemic 4-aryl(heteroary)-1,4-dihydro-2,6-dimethyl-3-nitropyridine-5-carboxylates possessing a potential nitric oxide donor C-5 O 2 -alkyl-1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate ester [alkyl ¼ (CH 2 ) n , n¼ 1-4] substituent were synthesized using a modified Hantzsch reaction. Compounds having a C-4 2-trifluoromethylphenyl (16), 2-pyridyl (17), or benzofurazan-4-yl (20) substituent generally exhibited more potent smooth-muscle calcium channel antagonist activity (IC 50 values in the 0.55 to 38.6 mM range) than related analogs having a C-4 3-pyridyl (18), or 4-pyridyl (19) substituent with IC 50 values 4 29.91 mM, relative to the reference drug nifedipine (IC 50 ¼ 0.0143 mM). The point of attachment of C-4 isomeric pyridyl substituents was a determinant of antagonist activity where the relative potency profile was 2-pyridyl 4 3-pyridyl and 4-pyridyl. Subgroups of compounds 16a-d, 17a-d, and 20a-d having alkyl spacer groups of variable chain length [-CO 2 (CH 2 ) n O-, n ¼ 1-4] exhibited small differences in calcium channel antagonist potency. Replacement of the ester ''methyl'' moiety of Bay K 8644 by an O 2 -alkyl-1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate group provided the Bay K 8644 group of analogs 16a-d that retained the desired cardiac positive inotropic effect. The most potent compound in this group, O 2 -ethyl-1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)pyridine-5-carboxylate (16b, EC 50 ¼ 0.096 mM) is about eightfold more potent positive inotrope (cardiac calcium channel agonist) than the reference compound Bay K 8644 (EC 50 ¼ 0.77 mM). A similar replacement of the ester ''isopropyl'' group in the C-4 benzofurazan-4-yl group of compounds by an O 2 -alkyl-1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate ester substituent provided compounds 20 (n ¼ 1 and 4) that were approximately equipotent cardiac positive inotropes with the parent reference compound PN 202-791 (3, EC 50 ¼ 9.40 mM). The O 2 -alkyl-1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate ester moiety present in 1,4-dihydropyridine calcium channel modulating compounds 16-20 is not a suitable NO donor moiety because the percent nitric oxide released upon in vitro incubation with either L-cysteine, rat serum, or pig liver esterase was less than 1%. Drug Dev. Res.