Analogues of sigma Receptor Ligand 1-Cyclohexyl-4[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]pip erazine (PB28) with Added Polar Functionality and Reduced Lipophilicity for Potential Use as Positron Emission Tomography Radiotracers

作者：Abate Carmen^*; Niso Mauro; Lacivita Enza; Mosier Philip D; Toscano Annamaria; Perrone Roberto

来源：Journal of Medicinal Chemistry, 2011, 54(4): 1022-1032.

DOI：10.1021/jm1013133

1-Cyclohexyl-4[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine 1 (PB28) represents an excellent lead candidate for therapeutic and/or diagnostic applications in oncology. However, because its utility is limited by its relatively high degree of lipophilicity, novel analogues of 1 with reduced lipophilic character were designed by substituting methylene groups with more polar functional groups in the propylene linker and at the tetralin C4 position. For the chiral analogues, separate enantiomers exhibited substantial and roughly equal affinities within a given receptor subtype, with the greatest difference observed for compound 9 at sigma(1) (7.5-fold; (-)-(S)-9 K(i) = 94.6 nM, (+)-(R)-9 K(i) = 12.6 nM). Compound (-)-(S)-9 was also found to be the most sigma(2)-selective agent (sigma(2) K(i) = 5.92 nM), to possess a lipophilicity consistent with entry into tumor cells (log D(7.4) = 2.38), and to show minimal antiproliferative activity. However, (-)-(S)-9 exhibited moderate activity (EC(50) = 8.1 mu M) at the P-gp efflux pump.

• 出版日期2011-2-24