A high affinity phenyl-piperidine P2Y14R antagonist (PPTN, 1) was modified with bridging moieties on the piperidine moiety to probe effects of constraint on receptor affinity and hydrophobicity. Enantiomeric 2-azabicyclo[2.2.1]hept-5-en-3-one precursors assured stereochemical unambiguity of the diverse products. Many of the 2-azanorborane, nortropane, isonortropane, and ring-opened cyclopentylamino derivatives preserved human P2Y14R affinity, as determined using a fluorescent binding assay. Pure (S,S,S) cis-2-azanorborane enantiomer (MRS4738, 14) displayed a lower IC50 than 1 (3-fold higher affinity than enantiomer 15). Related lactams (19–22) displayed intermediate affinity and enhanced aqueous solubility. An isonortropanol (MRS4679, 31) with a hydroxy-piperidinyl group showed IC50 21.3 nM and lower lipophilicity than 1. In general, derivatives with rigidified piperidines did not lower lipophilicity dramatically, except those rings with multiple polar groups. P2Y14R molecular modeling based on homology to the P2Y12R structure showed greater stability and persistence of key interactions for potent antagonist 14 compared to the weaker antagonist isonortropane 33.

Bridged piperidine analogues of a high affinity naphthalene-based P2Y14R antagonist

ACS Spring Meeting 2021

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