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
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Bibliographic record
Abstract
Abstract 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 μM 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 ≥ 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=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 μM range) relative to the reference drug Bay K 8644 IC 50 =0.77 μM). 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. © 2002 Wiley‐Liss, Inc.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.004 | 0.008 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.000 | 0.001 |
| 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 it