Synthesis, Biological Evaluation, and Molecular Modeling of New 3-(Cyclopentyloxy)-4-methoxybenzaldehyde O-(2-(2,6-Dimethylmorpholino)-2-oxoethyl) Oxime (GEBR-7b) Related Phosphodiesterase 4D (PDE4D) Inhibitors

Abstract

A new series of 3-(cyclopentyloxy)-4-methoxyphenyl derivatives, structurally related to our hit GEBR-4a (1) and GEBR-7b (2), has been designed by changing length and functionality of the chain linking the catecholic moiety to the terminal cycloamine portion. Among the numerous molecules synthesized, compounds 8, 10a, and 10b showed increased potency as PDE4D enzyme inhibitors with respect to 2 and a good selectivity against PDE4A4, PDE4B2, and PDE4C2 enzymes, without both cytotoxic and genotoxic effects. The ability to enhance cAMP level in neuronal cells was assessed for compound 8. SAR considerations, also confirmed by in silico docking simulations, evidenced that both chain and amino terminal function characterized by higher hydrophilicity are required for a good and selective inhibitor-catalytic pocket interaction.

Synthesis, biological activities and pharmacokinetic properties of new fluorinated derivatives of selective PDE4D inhibitors

“…Such observations could explain the decreased selectivity of compounds 1b and 2b in comparison with their isoster 5b and 6b. 19 On the other hand, the in silico calculations on PDE4B and PDE4D interaction with our previous compounds were not particularly explicatory and only gave an approximate picture of the ligand-enzyme interaction phenomenon, which is actually very complex and influenced by many different factors.…”

“…19 We used the same method also for the synthesis of the 4-(3-chloropropanoyl)-2,6-dimethyl-morpholine, while, 1-(chloroacetyl)piperidin-4-ol was prepared from 4-hydroxypiperidine and chloroacetyl chloride in the presence of a sodium carbonate saturated solution/ethyl acetate mixture (1:2), as previously reported in the literature. 34 …”

“…All compounds were tested in duplicate at the concentration of 10 lM, as previously reported and briefly described in the Section 4. 19 Subsequently, all compounds showing percent of inhibition higher than 50% were tested on PDE4D3 at five concentrations (5 Â 10 À8 -10 À4 M) and IC 50 values were determined by non linear regression analysis of their inhibition curves.…”

“…16 Our research on PDE4Is led to several series of small molecules structurally related to rolipram and characterized by good and selective PDE4D inhibition. [17][18][19] Among them, compound GEBR7b (7b, Fig. 1) increased memory performances in the object location test (OLT) and the object recognition test (ORT) in rodents, 13 and improved spatial memory in the APPswe/PS1dE9 mouse model of Alzheimer's disease (AD).…”

Efficient Syntheses of 1,2,3-Triazoloamide Derivatives Using Solid- and Solution-Phase Synthetic Approaches

“…The chloroamides 15 [31][32][33][34][35][36][37] were prepared from the reaction of secondary amines 14 (the first diversity elements R 1 and R 2 ; Figure 6) and chloro-acid chlorides 6a and 6c (the second diversity element A; see Figure 3) with triethylamine in CH2Cl2 at room temperature (99%-92% yields). Followed by SN2 reaction of tertiary amides 15 with sodium azide to generated the corresponding azidoamides 16 [15,17,[38][39][40][41] in high yields (99%-94% yields) ( Figure 7).…”