2. Academic Validation
  3. Use of a Conformational-Switching Mechanism to Modulate Exposed Polarity: Discovery of CCR2 Antagonist BMS-741672

Use of a Conformational-Switching Mechanism to Modulate Exposed Polarity: Discovery of CCR2 Antagonist BMS-741672

  • ACS Med Chem Lett. 2019 Jan 16;10(3):300-305. doi: 10.1021/acsmedchemlett.8b00439.
Michael G Yang 1,  Zili Xiao 1,  Robert J Cherney 1,  Andrew J Tebben 1,  Douglas G Batt 1,  Gregory D Brown 1,  Jing Chen 1,  Mary Ellen Cvijic 1,  Marta Dabros 1,  John V Duncia 1,  Michael Galella 1,  Daniel S Gardner 1,  Purnima Khandelwal 1,  Soo S Ko 1,  Mary F Malley 1,  Ruowei Mo 1,  Jian Pang 1,  Anne V Rose 1,  Joseph B Santella 3rd 1,  Hong Shi 1,  Anurag Srivastava 1,  Sarah C Traeger 1,  Bei Wang 1,  Songmei Xu 1,  Rulin Zhao 1,  Joel C Barrish 1,  Sandhya Mandlekar 1,  Qihong Zhao 1,  Percy H Carter 1
Affiliations

Affiliation

  • 1 Bristol-Myers Squibb Company, Research and Development, Route 206 and Province Line Road, Princeton, New Jersey 08543, United States.
PMID: 30891130 DOI: 10.1021/acsmedchemlett.8b00439
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.

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