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.

A group of 3-nitrooxyalkyl 5-alkyl 1,4-dihydro-2,6-dimethyl-4-(pyridyl)-3,5-pyridinedicarboxylates were prepared using a modified Hantzsch reaction that involved the condensation of a nitrooxyalkyl acetoacetate with an alkyl 3-aminocrotonate and a pyridinecarboxaldehyde. 1 H NMR nuclear Overhauser enhancement (nOe) studies for 3-(3-nitrooxypropyl) 5-isopropyl 1,4-dihydro-2,6-dimethyl-4-(2-pyridyl)-3,5-pyridinedicarboxylate (17) indicates a predominant rotamer exists in solution where the pyridyl nitrogen atom is orientated above the 1,4-DHP ring system, and the pyridyl nitrogen atom is antiperiplanar to the 1,4-DHP ring H-4 proton. Variable temperature 1 H NMR studies (-30 to +60°C) showed the 1,4-DHP NH proton in 17 is H-bonded in CHCl 3 solution. This interaction is believed to be due to intermolecular H-bonding between the pyridyl nitrogen free electron pair and the 1,4-DHP NH proton. In vitro calcium channel antagonist (CCA) activities were determined using a muscarinic-receptor-mediated Ca +2 -dependent contraction of guinea pig ileal longitudinal smooth muscle assay. This class of compounds exhibited lower CCA activity (IC 50 = 5.3 × 10 -6 to 3.5 × 10 -8 M range) than the reference drug nifedipine (IC 50 = 1.4 × 10 -8 M). For compounds having C-3 -CH 2 CH 2 ONO 2 and C-4 pyridyl substituents, the C-5 alkyl was a determinant of CCA (i-Pr > the approximately equipotent i-Bu, t-Bu, and Et analogs). The point of attachment of the isomeric C-4 pyridyl substituent was a determinant of CCA when C-3 -CH 2 CH 2 ONO 2 and C-5 i-Pr substituents were present providing the potency profile 2-pyridyl ≥ 3-pyridyl > 4-pyridyl. CCA with respect to the C-3 nitrooxyalkyl substituent was inversely dependent on the length of the alkyl spacer. The percent nitric oxide (•NO) released in vitro by this group of compounds (range of 0.03-0.43%/ONO 2 group), quantified as nitrite by reaction with the Griess reagent, was lower than that for the reference drug glycerol trinitrate (3.81%/ONO 2 group). Nitric oxide release studies showed that the %•NO released was dependent on the number of ONO 2 groups/molecule. A QSAR study for this group of compounds showed a correlation between the specific polarizability descriptor (SpPol) and %•NO release. Drug Dev. Res. 51:233-243, 2000.

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.

A group of isopropyl 1,4‐dihydro‐2,6‐dimethyl‐3‐nitro‐4‐phenylpyridine‐5‐carboxylates (13–15) possessing ortho‐, meta‐, and para‐CH2S(O)nMe and –S(O)nMe (n = 0–2) phenyl substituents were synthesized using a modified Hantzsch reaction. Calcium channel (CC) modulating activities were determined using guinea pig ileum longitudinal smooth muscle (GPILSM) and guinea pig left atrium (GPLA) in vitro assays. This class of –CH2S(O)nMe and –S(O)nMe (n = 0–2) compounds (13–15a–f) exhibited weaker CC antagonist activity on GPILSM (IC50 = > 1.1 × 10–5 to 4.1 × 10–6 M range) than the reference drug nifedipine (IC50 = 1.4 × 10–8 M). The oxidation state of the sulfur atom was a determinant of smooth muscle CC antagonist activity where the relative activity profile was generally thio (13, ‐CH2SMe, ‐SMe) and sulfonyl (15, ‐CH2SO2Me, ‐SO2Me) > sulfinyl (14, ‐CH2SOMe, ‐SOMe). The point of attachment of the phenyl substituent was a determinant of activity for the –CH2SMe (13a–c), ‐CH2SOMe (14a–c) and SOMe (14d–f) isomers where the relative potency order was meta and para > ortho. Compounds in this group (13–15), unlike Bay K 8644 (EC50 = 2.3 × 10–7 M on GPILSM), did not exhibit an agonist effect on GPILSM. The meta‐CH2SMe (13b), ortho‐CH2SMe (13c), meta‐SMe (13e), and ortho‐CH2SO2Me (15c) C‐4 phenyl derivatives exhibited respectable in vitro cardiac positive inotropic activities (EC50 = 1.00 × 10–6 to 7.57 × 10–6 M range) relative to the reference drug Bay K 8644 (EC50 = 7.70 × 10–7 M) in the GPLA assay. In contrast to Bay K 8644, which acts as an undesirable calcium channel agonist on smooth muscle (GPILSM), compounds 13b (IC50 = 4.11 × 10–6 M), 13c (IC50 = 2.29 × 10–5 M), 13e (IC50 = > 1.20 × 10–5 M) and 15c (IC50 = 6.22 × 10–6 M) exhibited a desirable simultaneous calcium channel antagonist effect on smooth muscle at a similar (13b, 15c), or lower (13c, 13e), concentration relative to its cardiac agonist EC50 value. Model compounds such as 13b, 13c, 13e, and 15c, that exhibit dual cardioselective agonist / smooth muscle selective antagonist activities, represent a novel type of 1,4‐dihydropyridine CC modulators that offer 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. 51:177–186, 2000. © 2001 Wiley‐Liss, Inc.

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The (+)- and (-)-enantiomers of 3-isopropyl 5-(4-methylphenethyl) 1,4-dihydro-2,6-dimethyl-4-(2-pyridyl)-3,5-pyridinedicarboxylate were synthesized using an efficient highly enantioselective (ee > or = to 96%) variant of the Hantzsch dihydropyridine synthesis. The key step in this procedure involved the asymmetric Michael addition of a metalated chiral aminocrotonate, derived from D-valine or L-valine, respectively, to the Knoevenagel acceptor (Z)-2-isopropoxycarbonyl-1-(2-pyridyl)-but-1-en-3-one. Both enantiomers exhibited a dual cardioselective partial calcium channel agonist (positive inotropic)/smooth muscle selective calcium channel antagonist effect. The relative in vitro smooth muscle calcium channel antagonist activities of the (-):(+) enantiomers was 26:1. In contrast, the (+)-enantiomer exhibited a greater in vitro positive inotropic effect on guinea pig left atrium where the contractile force was maximally increased by 14.8% at a concentration of 1.63 x 10(-8)M.

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