ArticleACS medicinal chemistry letters2019
Use of a Conformational-Switching Mechanism to Modulate Exposed Polarity: Discovery of CCR2 Antagonist BMS-741672.
Article in ACS medicinal chemistry letters, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
7 citing papers in PubMed.
- Molecular determinants of antagonist interactions with chemokine receptors CCR2 and CCR5.bioRxiv : the preprint server for biology · 2024Article
- Molecular chameleons in drug discovery.Nature reviews. Chemistry · 2024Review
- Peripheral CCL2-CCR2 signalling contributes to chronic headache-related sensitization.Brain : a journal of neurology · 2023Article
- Macrocycles in Drug Discovery─Learning from the Past for the Future.Journal of medicinal chemistry · 2023Review
- Review
- BMS-813160: A Potent CCR2 and CCR5 Dual Antagonist Selected as a Clinical Candidate.ACS medicinal chemistry letters · 2021Article
- Discovery of BMS-753426: A Potent Orally Bioavailable Antagonist of CC Chemokine Receptor 2.ACS medicinal chemistry letters · 2021Article
Corrections and comments
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Authors and funding
29 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
We encountered a dilemma in the course of studying a series of antagonists of the G-protein coupled receptor CC chemokine receptor-2 (CCR2): compounds with polar C3 side chains exhibited good ion channel selectivity but poor oral bioavailability, whereas compounds with lipophilic C3 side chains exhibited good oral bioavailability in preclinical species but poor ion channel selectivity. Attempts to solve this through the direct modulation of physicochemical properties failed. However, the installation of a protonation-dependent conformational switching mechanism resolved the problem because it enabled a highly selective and relatively polar molecule to access a small population of a conformer with lower polar surface area and higher membrane permeability. Optimization of the overall properties in this series yielded the CCR2 antagonist BMS-741672 (
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Registered trials
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