2. Academic Validation
  3. 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

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

Affiliation

  • 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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