Design of Novel Mercapto-3-phenylpropanoyl Dipeptides as Dual Angiotensin-Converting Enzyme C–Domain-Selective/Neprilysin Inhibitors
Bibliographic record
Abstract
High Resolution Image Download MS PowerPoint Slide Dual angiotensin-converting enzyme (ACE) and neprilysin (NEP) inhibitors such as omapatrilat showed promise as potent treatments for hypertension but produced adverse effects due to their high affinity for both domains of ACE (nACE and cACE). This led to the search for compounds that retained NEP potency but selectively inhibit cACE, leaving nACE active to degrade other peptides such as bradykinin. Lisinopril-tryptophan (LisW) has previously been reported to have cACE selectivity. Three mercapto-3-phenylpropanoyl inhibitors were synthesized, combining features of omapatrilat and LisW to probe structural characteristics required for potent dual cACE/NEP inhibition. We report the synthesis of these inhibitors, enzyme inhibition data, and high-resolution crystal structures in complex with nACE and cACE. This provides valuable insight into factors driving potency and selectivity and shows that the mercapto-3-phenylpropanoyl backbone is significantly better for NEP potency than a P 1 carboxylate. Future chemistry efforts could be directed at identifying alternative chemotypes for optimization of cACE/NEP inhibitors.
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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 | 0.001 | 0.001 |
| 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 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| 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".