Discovery of Novel Pyrido[2,3‐<i>b</i>]Pyrazine Human Cytomegalovirus Polymerase Inhibitors with Broad Spectrum Antiherpetic Activity and Reduced hERG Inhibition
Bibliographic record
Abstract
Abstract The development of non‐nucleoside inhibitors targeting human cytomegalovirus (HCMV) polymerase presents a promising approach for enhancing therapeutic treatment for patients with sustained HCMV viremia. A series of non‐nucleoside HCMV DNA polymerase inhibitors with various substitution groups at 2‐postition of the novel pyrido[2,3‐ b ]pyrazine core was synthesized and investigated. The study focused on optimizing HCMV polymerase inhibition while minimizing off‐target inhibition of human ether‐à‐go‐go (hERG) ion channel. Several compounds exhibited strong antiviral activity against HCMV (typical EC 50 <1 μM), with favorable cytotoxicity profiles. A potent lead compound, 27 , with an EC 50 of 0.33 μM and improved aqueous solubility was identified. Further antiviral assessments revealed the potential of select compounds to target a broad spectrum of herpesviruses, including herpes simplex virus (HSV‐1, HSV‐2) and Epstein‐Barr virus (EBV).
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How this classification was reachedexpand
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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".