ACS Medicinal Chemistry Letters · 2019 · 17 citations · 15 references
MedicineMedicinal ChemistryPharmacologyDrug DesignDrug DiscoveryMolecular PharmacologyDrug-receptor InteractionsG Protein-coupled Receptor SignalingIon Channel PharmacologyLigand BindingReceptor PharmacologyReceptor-ligand InteractionsChemokine Receptor AntagonismChemokine Receptor PharmacologyG Protein-coupled Chemokine ReceptorsHydrophobicity ModulationIon Channel SelectivityMolecular Property-based DesignOral Drug BioavailabilityPhysicochemical Properties
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 (7), which embodied properties suitable for study in human clinical trials.
15
Therapeutic siRNA silencing in inflammatory monocytes in mice
Florian Leuschner, Partha Dutta, Rostic Gorbatov et al. · Nature Biotechnology · 2011 · 837 citations · Full text
Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists
Yi Zheng, Ling Qin, Natalia V. Ortiz Zacarı́as et al. · Nature · 2016 · 296 citations · Full text