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Hantzsch 1,4‐dihydropyridines containing a nitrooxyalkyl ester moiety to study calcium channel antagonist structure–activity relationships and nitric oxide release
Author(s) -
Nguyen JeffreyTri,
McEwen CarolAnne,
Knaus Edward E.
Publication year - 2000
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.4
Subject(s) - chemistry , stereochemistry , moiety , isopropyl , medicinal chemistry
Abstract 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 N H 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 N H 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. © 2001 Wiley‐Liss, Inc.