Use of a Conformational-Switching Mechanism to Modulate Exposed Polarity: Discovery of CCR2 Antagonist BMS-741672
| Autor: | Mary Ellen Cvijic, Andrew J. Tebben, Jian Pang, Mary F. Malley, Ruowei Mo, Joseph B. Santella, Songmei Xu, Qihong Zhao, Douglas G. Batt, Jing Chen, Anne Rose, Bei Wang, Hong Shi, Marta Dabros, Anurag S. Srivastava, Percy H. Carter, Purnima Khandelwal, Yang Michael G, Gardner Daniel S, Gregory D. Brown, Sandhya Mandlekar, Michael Galella, Rulin Zhao, Zili Xiao, John V. Duncia, Sarah C. Traeger, Joel C. Barrish, Robert J. Cherney, Soo S. Ko |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
education.field_of_study
Membrane permeability 010405 organic chemistry Chemistry Organic Chemistry Population 01 natural sciences Biochemistry 0104 chemical sciences Polar surface area Bioavailability 010404 medicinal & biomolecular chemistry Drug Discovery Side chain Biophysics Selectivity education Conformational isomerism Ion channel |
| Zdroj: | ACS Medicinal Chemistry Letters. 10:300-305 |
| ISSN: | 1948-5875 |
| DOI: | 10.1021/acsmedchemlett.8b00439 |
| Popis: | [Image: see text] 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|