From rigid cyclic templates to conformationally stabilized acyclic scaffolds. Part II: Acyclic replacements for the (3S)-3-benzylpiperidine in a series of potent CCR3 antagonists

Daniel S Gardner; Joseph B Santella 3rd; Andrew J Tebben; Douglas G Batt; Soo S Ko; Sarah C Traeger; Patricia K Welch; Eric A Wadman; Paul Davies; Percy H Carter; John V Duncia

doi:10.1016/j.bmcl.2007.11.087

From rigid cyclic templates to conformationally stabilized acyclic scaffolds. Part II: Acyclic replacements for the (3S)-3-benzylpiperidine in a series of potent CCR3 antagonists

Bioorg Med Chem Lett. 2008 Jan 15;18(2):586-95. doi: 10.1016/j.bmcl.2007.11.087. Epub 2007 Nov 28.

Authors

Daniel S Gardner¹, Joseph B Santella 3rd, Andrew J Tebben, Douglas G Batt, Soo S Ko, Sarah C Traeger, Patricia K Welch, Eric A Wadman, Paul Davies, Percy H Carter, John V Duncia

Affiliation

¹ Bristol-Myers Squibb Company, R & D, PO Box 4000, Princeton, NJ 08543-4000, USA.

PMID: 18160284
DOI: 10.1016/j.bmcl.2007.11.087

Abstract

Conformational analysis of the 3-benzylpiperidine in CCR3 antagonist clinical candidate 1 (BMS-639623) predicts that the benzylpiperidine may be replaced by acyclic, conformationally stabilized, anti-1,2-disubstituted phenethyl- and phenpropylamines. Ab initio calculations, enantioselective syntheses, and evaluation in CCR3 binding and chemotaxis assays of anti-1-methyl-2-hydroxyphenethyl- and phenpropylamine-containing CCR3 antagonists support this conformational correlation.

MeSH terms

Cyclization
Hydrogen Bonding
Molecular Conformation
Piperidines / chemistry*
Piperidines / pharmacology*
Receptors, CCR3 / antagonists & inhibitors*
Urea / analogs & derivatives*
Urea / chemistry
Urea / pharmacology

Substances

BMS-639623
CCR3 protein, human
Piperidines
Receptors, CCR3
Urea