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Synthesis and Pharmacological Evaluation of 1,8-Naphythyridin-2(1H)-one-3-carboxamides Derivatives as Cannabinoid Receptor Type 2 (CB2R) Ligands

Kaur, S.

The primary aim of the present work was to develop fluorinated containing CB2R
ligands based on the lead compound 26 (Figure 10), reported by Lucchesi et al. with
a binding affinity of Ki(CB2R)< 0.67 nM and Ki(CB1R)>5140 nM [91]. Although the
lead compound 26 had a remarkable binding activity it has rather unfavorable
pharmacological properties (cLogP = 4.99 and MW = 459.52 g/mol). Most of the
compounds with cLogP>5 and MW >500 g/mol have poor absorption due to low
solubility and are also unable to cross BBB resulting in poor pharmacokinetics.
Therefore, this master thesis was aimed to synthesize new derivatives based on the
lead compound 26 with modifications to retain or further increase the CB2R binding
affinity and selectivity and improve the pharmacological properties by introducing
substituents containing electronegative atom (fluoro pyridine, fluoro alkoxy, etc) to
make them more polar and thereby also reducing their molecular weight. In general,
the research work was primarily aimed to variously functionalize at N-1 position. In
addition, the newly derivatized compounds should contain a fluorine atom at a
position that allows a facile incorporation of the 18F-label. The cLogP of the planned
derivatives was calculated (ChemDraw 19.0 software) to analyze the effect of
various substituents on the lipophilicity. The substitution of furyl group with a Br at
C-6 position was aimed to increase the hydrophilicity of the lead compound 26
leading to the bromo substituted derivatives with cLogP < 4.5. In order to further
decrease the lipophilicity of the lead compound (26), the replacement of the pfluorobenzyl
at N-1 position with pyridine (cLogP= 3.57) and alkoxy derivatives
(cLogP= 3.72) was planned to synthesize new derivatives (X= R1: furyl, R2:
fluoropyridine, fluoroalkoxy).

  • Master thesis
    Universität Leipzig, 2021
    Mentor: Prof. Bachmann
    78 Seiten

Publ.-Id: 33128