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Record W2000546717 · doi:10.1021/ml500002n

Discovery of BI 224436, a Noncatalytic Site Integrase Inhibitor (NCINI) of HIV-1

2014· article· en· W2000546717 on OpenAlexaff
Lee D. Fader, Éric Malenfant, Mathieu Parisien, Rebekah Carson, François Bilodeau, Serge Landry, Marc Pesant, Christian Brochu, Sébastien Morin, Catherine Chabot, Ted Halmos, Yves Bousquet, Murray D. Bailey, Stephen H. Kawai, René Coulombe, Steven R. LaPlante, Araz Jakalian, Punit Kumar Bhardwaj, Dominik Wernic, Patricia Schroeder, Ma’an Amad, Paul Edwards, Michel Garneau, Jianmin Duan, Michael G. Cordingley, Richard C. Bethell, Stephen W. Mason, Michael Bös, Pierre Bonneau, Marc‐André Poupart, Anne‐Marie Faucher, Bruno Simoneau, Craig Fenwick, Christiane Yoakim, Youla S. Tsantrizos

Bibliographic record

VenueACS Medicinal Chemistry Letters · 2014
Typearticle
Languageen
FieldMedicine
TopicHIV/AIDS drug development and treatment
Canadian institutionsBoehringer Ingelheim (Canada)
Fundersnot available
KeywordsPotencyIntegraseSubstituentHuman immunodeficiency virus (HIV)QuinolineIntegrase inhibitorPharmacologyChemistryVirologyMedicineStereochemistryComputational biologyBiologyBiochemistryIn vitroAntiretroviral therapyViral load

Abstract

fetched live from OpenAlex

An assay recapitulating the 3' processing activity of HIV-1 integrase (IN) was used to screen the Boehringer Ingelheim compound collection. Hit-to-lead and lead optimization beginning with compound 1 established the importance of the C3 and C4 substituent to antiviral potency against viruses with different aa124/aa125 variants of IN. The importance of the C7 position on the serum shifted potency was established. Introduction of a quinoline substituent at the C4 position provided a balance of potency and metabolic stability. Combination of these findings ultimately led to the discovery of compound 26 (BI 224436), the first NCINI to advance into a phase Ia clinical trial.

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 imitation

Not 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.

metaresearch head score (Codex)0.000
metaresearch head score (Gemma)0.000
Version: codex-gemma-dda1882f352aValidation status: machine_predicted_unvalidated
Candidate categoriesnone
Consensus categoriesnone
DomainCandidate signal: none · Consensus signal: none
Study designCandidate signal: Bench or experimental · Consensus signal: Bench or experimental
GenreCandidate signal: Empirical · Consensus signal: Empirical
Teacher disagreement score0.042
Threshold uncertainty score0.817

Codex and Gemma teacher scores by category

CategoryCodexGemma
Metaresearch0.0000.000
Meta-epidemiology (narrow)0.0000.000
Meta-epidemiology (broad)0.0010.000
Bibliometrics0.0000.000
Science and technology studies0.0000.000
Scholarly communication0.0000.000
Open science0.0000.000
Research integrity0.0000.000
Insufficient payload (model declined to judge)0.0000.000

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.

Opus teacher head0.006
GPT teacher head0.226
Teacher spread0.219 · how far apart the two teachers sit on this one work
Validation statusscore_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it

Classification

machine, unvalidated

Machine predicted; a candidate call from one teacher head, not a consensus.

The models applied no category: nothing in the taxonomy fit this work.
Study designBench or experimental
Domainnot available
GenreEmpirical

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".

Quick stats

Citations180
Published2014
Admission routes1
Has abstractyes

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