2. Academic Validation
  3. Discovery of BMS-753426: A Potent Orally Bioavailable Antagonist of CC Chemokine Receptor 2

Discovery of BMS-753426: A Potent Orally Bioavailable Antagonist of CC Chemokine Receptor 2

  • ACS Med Chem Lett. 2021 May 25;12(6):969-975. doi: 10.1021/acsmedchemlett.1c00082.
Michael G Yang 1,  Zili Xiao 1,  Rulin Zhao 1,  Andrew J Tebben 1,  Bei Wang 1,  Robert J Cherney 1,  Douglas G Batt 1,  Gregory D Brown 1,  Mary Ellen Cvijic 1,  John V Duncia 1,  Michael A Gallela 1,  Daniel S Gardner 1,  Purnima Khandelwal 1,  Mary F Malley 1,  Jian Pang 1,  Anne V Rose 1,  Joseph B Santella 3rd 1,  Amy A Sarjeant 1,  Songmei Xu 1,  Arvind Mathur 1,  Sandhya Mandlekar 1,  Ragini Vuppugalla 1,  Qihong Zhao 1,  Percy H Carter 1
Affiliations

Affiliation

  • 1 Research and Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.
PMID: 34141082 DOI: 10.1021/acsmedchemlett.1c00082
Abstract

To improve the metabolic stability profile of BMS-741672 (1a), we undertook a structure-activity relationship study in our trisubstituted cyclohexylamine series. This ultimately led to the identification of 2d (BMS-753426) as a potent and orally bioavailable antagonist of CCR2. Compared to previous clinical candidate 1a, the tert-butyl amine 2d showed significant improvements in pharmacokinetic properties, with lower clearance and higher oral bioavailability. Furthermore, compound 2d exhibited improved affinity for CCR5 and good activity in models of both monocyte migration and multiple sclerosis in the hCCR2 knock-in mouse. The synthesis of 2d was facilitated by the development of a simplified approach to key intermediate (4R)-9b that deployed a stereoselective reductive amination which may prove to be of general interest.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-115874
    CCR Antagonist
    CCR