Hantzsch 1,4‐dihydropyridines containing a nitrooxyalkyl ester moiety to study calcium channel antagonist structure–activity relationships and nitric oxide release
Bibliographic record
Abstract
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. 1H 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 1H NMR studies (–30 to +60°C) showed the 1,4‐DHP NH proton in 17 is H‐bonded in CHCl3 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 (IC50 = 5.3 × 10–6 to 3.5 × 10–8 M range) than the reference drug nifedipine (IC50 = 1.4 × 10–8 M). For compounds having C‐3 –CH2CH2ONO2 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 –CH2CH2ONO2 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%/ONO2 group), quantified as nitrite by reaction with the Griess reagent, was lower than that for the reference drug glycerol trinitrate (3.81%/ONO2 group). Nitric oxide release studies showed that the %·NO released was dependent on the number of ONO2 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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".