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Structure-activity relationship around PI-2620 highlights the importance of the nitrogen atom position in the tricyclic core
Heiko Kroth, Felix Oden, Andreia Monica Serra, Jerome Molette, Andre Mueller, Mathias Berndt, Francesca Capotosti, Emanuele Gabellieri et al.. Bioorganic & medicinal chemistry, 2021-11-20
Topic: Disease mechanisms in lab and animal studies
Tau aggregates represent a critical pathology in Alzheimer's disease (AD) and other forms of dementia. The extent of Tau neurofibrillary tangles across defined brain regions corresponds well to the observed level of cognitive decline in AD. Compound 1 (PI-2620) was recently identified as a promising Tau positron emission tomography tracer for AD and non-AD tauopathies. To evaluate the impact of the N-atom position with respect to Tau- and off-target binding, tricyclic core analogs of PI-2620 with nitrogen atoms at different positions were prepared. Affinity to aggregated Tau was evaluated using human AD brain homogenates, and their off-target binding was evaluated in a monoamine oxidase A (MAO-A) competition assay. The novel tricyclic core derivatives all displayed inferior Tau binding or MAO-A off-target selectivity, indicating PI-2620 to be the optimal design for high affinity binding to Tau and high MAO-A selectivity.
Key findings
- The extent of Tau neurofibrillary tangles across defined brain regions corresponds well to the observed level of cognitive decline in AD.
- Compound 1 (PI-2620) was recently identified as a promising Tau positron emission tomography tracer for AD and non-AD tauopathies.
- To evaluate the impact of the N-atom position with respect to Tau- and off-target binding, tricyclic core analogs of PI-2620 with nitrogen atoms at different positions were prepared.
- Affinity to aggregated Tau was evaluated using human AD brain homogenates, and their off-target binding was evaluated in a monoamine oxidase A (MAO-A) competition assay.
- The novel tricyclic core derivatives all displayed inferior Tau binding or MAO-A off-target selectivity, indicating PI-2620 to be the optimal design for high affinity binding to Tau and high MAO-A selectivity.
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Study details
- Evidence strengthLow
How this study scored 41/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record, multi-centre collaboration and free to read, so those were left out: it earned 23 of the 56 points we could judge it on, which is 41 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Bioorganic & medicinal chemistry) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 3 / 5 | 2021 — within 6 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 34839158) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 23 / 56 | Scored on 10 of 20 parts. We have no data for the rest, so they are left out: 23 of the 56 points we could judge it on is 41 out of 100. |
| Total | 41 / 100 | — |
What each of these 20 components measures, and what this score is not →
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
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APA 7th
Kroth, H., Oden, F., Serra, A. M., Molette, J., Mueller, A., Berndt, M., et al. (2021). Structure-activity relationship around PI-2620 highlights the importance of the nitrogen atom position in the tricyclic core. Bioorganic & medicinal chemistry. https://doi.org/10.1016/j.bmc.2021.116528
Vancouver
Kroth H, Oden F, Serra AM, Molette J, Mueller A, Berndt M, et al. Structure-activity relationship around PI-2620 highlights the importance of the nitrogen atom position in the tricyclic core. Bioorganic & medicinal chemistry. 2021. doi:10.1016/j.bmc.2021.116528. PMID: 34839158.
BibTeX
@article{kroth2021-34839158,
author = {Kroth, Heiko and Oden, Felix and Serra, Andreia Monica and Molette, Jerome and Mueller, Andre and Berndt, Mathias and Capotosti, Francesca and Gabellieri, Emanuele and others},
title = {{Structure-activity relationship around PI-2620 highlights the importance of the nitrogen atom position in the tricyclic core}},
journal = {Bioorganic \& medicinal chemistry},
year = {2021},
doi = {10.1016/j.bmc.2021.116528},
pmid = {34839158},
url = {https://doi.org/10.1016/j.bmc.2021.116528}
}
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