| Literature DB >> 31986033 |
Sean Henry1, Jessica P Anand2,3, Jack J Twarozynski2,3, Ashley C Brinkel2,3, Irina D Pogozheva1, Bryan F Sears2,3, Emily M Jutkiewicz2,3, John R Traynor1,2,3, Henry I Mosberg1,3.
Abstract
We previously reported a novel SAR campaign that converted a metabolically unstable series of μ-opioid receptor (MOR) agonist/δ-opioid receptor (DOR) antagonist bicyclic core peptidomimetics with promising analgesic activity and reduced abuse liabilities into a more stable series of benzylic core analogues. Herein, we expanded the SAR of that campaign and determined that the incorporation of amines into the benzylic pendant produces enhanced MOR-efficacy in this series, whereas the reincorporation of an aromatic ring into the pendant enhanced MOR-potency. Two compounds, which contain a piperidine (14) or an isoindoline (17) pendant, retained the desired opioid profile in vitro, possessed metabolic half-lives of greater than 1 h in mouse liver microsomes (MLMs), and were active antinociceptive agents in the acetic acid stretch assay (AASA) at subcutaneous doses of 1 mg/kg.Entities:
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Year: 2020 PMID： 31986033 PMCID： PMC7047604 DOI： 10.1021/acs.jmedchem.9b01818
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446