| Literature DB >> 30891130 |
Michael G Yang1, Zili Xiao1, Robert J Cherney1, Andrew J Tebben1, Douglas G Batt1, Gregory D Brown1, Jing Chen1, Mary Ellen Cvijic1, Marta Dabros1, John V Duncia1, Michael Galella1, Daniel S Gardner1, Purnima Khandelwal1, Soo S Ko1, Mary F Malley1, Ruowei Mo1, Jian Pang1, Anne V Rose1, Joseph B Santella1, Hong Shi1, Anurag Srivastava1, Sarah C Traeger1, Bei Wang1, Songmei Xu1, Rulin Zhao1, Joel C Barrish1, Sandhya Mandlekar1, Qihong Zhao1, Percy H Carter1.
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 (7), which embodied properties suitable for study in human clinical trials.Entities:
Year: 2019 PMID： 30891130 PMCID： PMC6421546 DOI： 10.1021/acsmedchemlett.8b00439
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345