Design And Synthesis Of Novel Biphenyl Derivatives As Phosphodiesterase ? Inhibitors

Phosphodiesterase 4(PDE4),a cyclic adenosine monophosphate(cAMP)specific hydrolyzing enzymes,may be a good target for inflammatory diseases and central nervous system(CNS)disorders.PDE4 inhibitors with good anti-depression,cognition enhancement and anti-neuroinflammation activities represent a novel therapeutic strategy for CNS disorders,such as depression and Alzheimer's disease.To discover PDE4 inhibitors with anti-neuroinflammation activities,reliable 3D-QSAR(Three-dimensional quantitative structure-activity relationship)study on reported catecholic and pyrazinone PDE4 inhibitors was performed.Based on the 3D-QSAR study,two new diphenyl derivatives were designed and synthesized,Their PDE4 inhibitor activity and anti-neuroinflammatory activity were evaluated.The details as follows:[1]3D-QSAR studies on our previously reported PDE4 inhibitorsIn this section,reliable 3D-QSAR models on our previously reported catecholicand pyrazinone PDE4 inhibitors were built using CoMFA(comparative molecular field analysis)and CoMSIA(comparative molecular similarity index analysis)methods.PLS statistics on CoMFA and COMSIA model displayed statistically significant cross-validated coefficients(q2,0.517 and 0.612 respectively),and conventional coefficient(r2,0.914 and 0.937 respectively)using 41 molecules in training set.Good predictive capabilities of CoMFA(r2pred=0.853)and COMSIA(r2pred=0.850)model were verified using a test set of 9 molecules.Based on the analysis of 3D-QSAR contour maps,structure-activity relationships of PDE4 inhibitors with high activity were derived as follow.[2]Design,synthesis and evaluation of novel biphenyl derivatives as phosphodiesterase ? inhibitorsBased on the above 3D-QSAR and the binding model of PDE4 inhibitors in the active cavity,29 new 3-aryl-4-alkoxybenzylamine derivatives and 36 new 3-aryl-4-alkoxybenzylether derivatives as PDE4inhibitors in this section,using selective PDE4 inhibitors FCPR03 and FCPR16 as lead compounds.Their inhibitory activities against PDE4CAT,PDE4B1,and PDE4D7 were also evaluated.Design and synthesis of 3-aryl-4-alkoxybenzylamine derivatives:The preliminary activity test displayed that compounds 73o,73u,73v,73w,73x,74a,74d,74e exhibited good inhibitory activities against PDE4CAT,PDE4B1,and PDE4D7.Moreover,compound 74a displayed anti-neuroinflammation potential.Compound 73u displayed the highest activities against PDE4B1(IC50=340 nM)and PDE4D7(IC50=370 nM)with the mid-nanomolar IC50 values.The docking simulation of compound 73u suggested the side chain extend to the M-pocket.The linking group(NH)forms hydrogen bonds with conserved water molecules in active site,which extends to the residue Asp484 and the metal coordination oxygen atom.In addition,the side chain forms a hydrogen bond a water molecule that is coordinated to Mg+.Further efforts will be aimed at more potent PDE4 inhibitors using compound 73u as a lead compound.Design and synthesis of 3-aryl-4-alkoxybenzylether derivatives:The preliminary activity test displayed that compounds 75v,75w,75x,75z,75G,75J exhibited good inhibitory activities against PDE4CAT,PDE4B1,and PDE4D7.Furthermore,PDE4D7inhibitory activities of these compounds were higher than their PDE4CAT and PDE4B1 inhibitory activities.Moreover,compound 75w displayed the highest activities against PDE4D7(IC50=1.8?M).The docking simulation of compound 75w suggested the side chain extend to the M-pocket.The extends to the residue Met439 and Asn375.Further efforts will be aimed at subtype-selective PDE4 inhibitors using compound 75w as a lead compound.