Design And Synthesis Of Novel Aminophenyl Ketone Derivatives As PDE4 Inhibitors

Phosphodiesterases 4(PDE4)is widely distributed in inflammatory cells and nervous tissues,and plays an important role in the physiological regulation of the central nervous system and immune system.Therefore,it can be used as a potential therapeutic target for inflammatory diseases and CNS disorders.In recent years,the good effects of PDE4 inhibitors on central nervous system diseases(depression,dementia,etc.)have made it a new strategy for the treatment of such diseases.Our group has previously discovered a highly selective PDE4 inhibitor FCPR03.This compound has a good ameliorated effect on the depression-like behavior of LPS-induced depression model mice and CUMS depression model mice,and there is no emesis at an effective dose in the Beagle dog vomiting model experiment.To obtain new PDE4 inhibitors with good developmental potentiality for the treatment of central nervous system diseases,we use FCPR03 as the lead compound,55 aminophenyl ketone derivatives A01-53 and B01-02 were designed by replacing the nitrogen atom of the side chain amide with a carbon atom,and replacing cyclopentylmethoxy with the secondary amine,tertiary amine or heterocyclic ring.The replacement of the nitrogen atom in FCPR03 with a carbon atom can increase fat solubility.All target compounds were synthesized and confirmed by 1H-NMR,13CNMR,and ESI-MS.Their inhibitory activities on PDE4B1 were tested.Preliminary screening results showed that most(41 compounds)of aminophenyl ketone derivatives showed moderate to better inhibitory activity on PDE4B1(0.1 1 μM<IC50<10 μM).Among these compounds,A02,A06,A17,A18,A19,A23,A40,A4244 exhibited sub-micromole IC50 values(0.1 1 μM<IC50<0.89 μM).Moreover,A19(IC50=0.12 μM)and A42(IC50=0.11 μM)exhibited the highest PDE4 ihibitory activities,which was comparable to that of the control drug rolipram(IC50=0.13 μM).Careful analysis of the structure-activity relationship(SAR)of aminophenyl ketones reveals that the substituents on the benzene ring have profound effects on the inhibitory activities of the compounds.First,the inhibitory activities decrease in the following order(except compounds A07,A15 and A16):CHF2O<EtO<MeO.In addition,the replacement of the alkoxy group(R1O)on the benzene ring with tetrahydrofuran ring leads to decreased activity.Secondly,aminophenyl ketones with R2R3 CHNH group displayed higher activities than their corresponding analogues with R2R3N group.For aminophenyl ketones with R2R3CHNH groups,the effect of R2R3CHNH groups on activities was irregular.Finally,the alkyl side chain size should be moderate.Replacing the isobutyl side chains with cyclohexyl,butyl and propyl side chains resulted in decreased inhibitory activity.When R2R3CHNH is an ethylamine group,the replacement of isobutyl side chain with the cyclopentyl side chain does not affect inhibitory activity.For aminophenyl ketones bearing(tetrahydrothiophen-3-yl)amino group,replacement of isobutyl side chain with the cyclopentyl side-chain leads to decreased inhibitory activity.For example,A41 bearing isobutyl side chain displayed higher inhibitory activity than A17 bearing cyclopentyl side chain.To understand the observed SAR,molecular docking studies of compounds A19 and A42 were performed in Maestro 11.1 with the coordinates of the crystal structure of PDE4B(1XMU).The molecular docking results showed that the carbonyl group of A19 and A42 were in the middle of the saddle-shaped hydrophobic Q pocket,made intermolecular hydrogen bond with glutamine(Gln443).Isobutyl side chain(A19)and cyclopentyl side chain(A42)extend in the direction of the Q1 pocket.Because of the small Q1 pocket,it is not suitable for the introduction of large groups.Consequently,the volume of the alkyl side chain should be moderate.Too large or too small is not good for its inhibitory activity.