Bridged Piperidine Analogues of a High Affinity Naphthalene-Based P2Y<sub>14</sub>R Antagonist.
Wen Z, Salmaso V, Jung YH, Phung NB, Gopinatth V, Shah Q, Patterson AT, Randle JCR, Chen Z, Salvemini D, Lieberman DI, Whitehead GS, Karcz TP, Cook DN, Jacobson KA.
High affinity phenyl-piperidine P2Y<sub>14</sub>R antagonist <b>1</b> (PPTN) was modified with piperidine bridging moieties to probe receptor affinity and hydrophobicity. Various 2-azanorbornane, nortropane, isonortropane, isoquinuclidine, and ring-opened cyclopentylamino derivatives preserved human P2Y<sub>14</sub>R affinity (fluorescence binding assay), and their pharmacophoric overlay was compared. Enantiomeric 2-azabicyclo[2.2.1]hept-5-en-3-one precursors assured stereochemically unambiguous, diverse products. Pure (<i>S</i>,<i>S</i>,<i>S</i>) 2-azanorbornane enantiomer <b>15</b> (MRS4738) displayed higher affinity than <b>1</b> (3-fold higher affinity than enantiomer <b>16</b>) and in vivo antihyperallodynic and antiasthmatic activity. Its double prodrug <b>143</b> (MRS4815) dramatically reduced lung inflammation in a mouse asthma model. Related lactams <b>21</b>-<b>24</b> and dicarboxylate <b>42</b> displayed intermediate affinity and enhanced aqueous solubility. Isoquinuclidine <b>34</b> (IC<sub>50</sub> 15.6 nM) and isonortropanol <b>30</b> (IC<sub>50</sub> 21.3 nM) had lower lipophilicity than <b>1</b>. In general, rigidified piperidine derivatives did not lower lipophilicity dramatically, except those rings with multiple polar groups. P2Y<sub>14</sub>R molecular modeling based on a P2Y<sub>12</sub>R structure showed stable and persistent key interactions for compound <b>15</b>.