Evaluation of WO2015042088 A1 - a novel urea-based scaffold for TrkA inhibition
Bibliographic record
Abstract
Tropomyosin receptor kinases (TrkA/B/C) are involved in the development and maintenance of the nervous system. TrkA is a target for chronic pain treatment due to the central position of the nerve growth factor (NGF)/TrkA pathway in nociception. Clinical evidence points toward mutated oncogenic Trk fusion proteins retaining intact kinase domains as relevant targets for cancer treatment. Merck pursues Trk inhibitors for inflammatory and neuropathic pain treatment and has previously reported type I and II selective pan-Trk inhibitors. This is the fifth filing by Merck disclosing urea-based Trk inhibitor series. This application claims nonsymmetric 1-(9H-fluoren-9-yl)urea and 1-(9H-xanthen-9-yl)urea derivatives containing a wide range of 5- and 6-membered bi- or tri-heterocyclic fragments as TrkA inhibitors for the treatment of Trk-related conditions. The exemplified compounds display IC50 values ranging from 27 to 4800 nM against TrkA. The TrkA inhibitors claimed confirm the emergence of nonsymmetric ureas lacking the hinge-binding motif as a favored Trk inhibitor structure. The compounds exemplified will likely be structurally optimized in the future. Despite the lack of selectivity profiling, the progression of the Trk inhibitor scaffold exploration by Merck also suggests that the compounds disclosed in this patent likely constitute non-adenosine triphosphate (ATP) competitive type III pan-Trk inhibitors.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.000 |
| 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) | 0.000 | 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".