High affinity phenyl-piperidine P2Y14R antagonist 1 (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 P2Y14R 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 (S,S,S) 2-azanorbornane enantiomer 15 (MRS4738)
displayed higher affinity than 1 (3-fold higher affinity
than enantiomer 16) and in vivo antihyperallodynic and
antiasthmatic activity. Its double prodrug 143 (MRS4815)
dramatically reduced lung inflammation in a mouse asthma model. Related
lactams 21–24 and dicarboxylate 42 displayed intermediate affinity and enhanced aqueous solubility.
Isoquinuclidine 34 (IC50 15.6 nM) and isonortropanol 30 (IC50 21.3 nM) had lower lipophilicity than 1. In general, rigidified piperidine derivatives did not lower
lipophilicity dramatically, except those rings with multiple polar
groups. P2Y14R molecular modeling based on a P2Y12R structure showed stable and persistent key interactions for compound 15.
A known zwitterionic, heterocyclic
P2Y14R antagonist 3a was substituted with
diverse groups on the central phenyl
and terminal piperidine moieties, following a computational selection
process. The most potent analogues contained an uncharged piperidine
bioisostere, prescreened in silico, while an aza-scan (central phenyl
ring) reduced P2Y14R affinity. Piperidine amide 11, 3-aminopropynyl 19, and 5-(hydroxymethyl)isoxazol-3-yl) 29 congeners in the triazole series maintained moderate receptor
affinity. Adaption of 5-(hydroxymethyl)isoxazol-3-yl gave the most
potent naphthalene-containing (32; MRS4654; IC50, 15 nM) and less active phenylamide-containing (33)
scaffolds. Thus, a zwitterion was nonessential for receptor binding,
and molecular docking and dynamics probed the hydroxymethylisoxazole
interaction with extracellular loops. Also, amidomethyl ester prodrugs
were explored to reversibly block the conserved carboxylate group
to provide neutral analogues, which were cleavable by liver esterase,
and in vivo efficacy demonstrated. We have, in stages, converted zwitterionic
antagonists into neutral molecules designed to produce potent P2Y14R antagonists for in vivo application.
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