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Bridged Piperidine Analogues of a High Affinity Naphthalene-Based P2Y

Authors :
Zhiwei, Wen
Veronica, Salmaso
Young-Hwan, Jung
Ngan B, Phung
Varun, Gopinatth
Qasim, Shah
Alexandra T, Patterson
John C R, Randle
Zhoumou, Chen
Daniela, Salvemini
David I, Lieberman
Gregory S, Whitehead
Tadeusz P, Karcz
Donald N, Cook
Kenneth A, Jacobson
Source :
J Med Chem
Publication Year :
2023

Abstract

High affinity phenyl-piperidine P2Y(14)R 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 P2Y(14)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 (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 (IC(50) 15.6 nM) and isonortropanol 30 (IC(50) 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. P2Y(14)R molecular modeling based on a P2Y(12)R structure showed stable and persistent key interactions for compound 15.

Details

ISSN :
15204804
Volume :
65
Issue :
4
Database :
OpenAIRE
Journal :
Journal of medicinal chemistry
Accession number :
edsair.pmid..........da62c41535c927994c70d1b42266cae7