From rigid cyclic templates to conformationally stabilized acyclic scaffolds. Part I: the discovery of CCR3 antagonist development candidate BMS-639623 with picomolar inhibition potency against eosinophil chemotaxis

  • Bioorg Med Chem Lett. 2008 Jan 15;18(2):576-85. doi: 10.1016/j.bmcl.2007.11.067.
Joseph B Santella 3rd  1 ,  Daniel S Gardner ,  Wenqing Yao ,  Chongsheng Shi ,  Prabhakar Reddy ,  Andrew J Tebben ,  George V DeLucca ,  Dean A Wacker ,  Paul S Watson ,  Patricia K Welch ,  Eric A Wadman ,  Paul Davies ,  Kimberly A Solomon ,  Dani M Graden ,  Swamy Yeleswaram ,  Sandhya Mandlekar ,  Ilona Kariv ,  Carl P Decicco ,  Soo S Ko ,  Percy H Carter ,  John V Duncia
Affiliations
  • 1. Bristol-Myers Squibb Company, R&D, PO Box 4000, Princeton, NJ 08543-4000, USA.
PMID: 18096386 DOI: 10.1016/j.bmcl.2007.11.067
Abstract

Conformational analysis of trans-1,2-disubstituted cyclohexane CCR3 Antagonist 2 revealed that the cyclohexane linker could be replaced by an acyclic syn-alpha-methyl-beta-hydroxypropyl linker. Synthesis and biological evaluation of mono- and disubstituted propyl linkers support this conformational correlation. It was also found that the alpha-methyl group to the urea lowered protein binding and that the beta-hydroxyl group lowered affinity for CYP2D6. Ab initio calculations show that the alpha-methyl group governs the spatial orientation of three key functionalities within the molecule. alpha-Methyl-beta-hydroxypropyl urea 31 with a chemotaxis IC(50)=38 pM for eosinophils was chosen to enter clinical development for the treatment of Asthma.

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