Study On The Design, Synthesis And Structure-activity Of Urea And Amide Derivatives As KCNQ2/Q3Potassium Channel Openers

Epilepsy is a common neurological disorder with numerous patients. Themajority of its patients cannot be cured with medication and has to rely ondrugs for preventing seizure. According to the research of voltage-gatedpotassium channel, KCNQ2/Q3could be a new target of antiepileptic.Retigabine as a specific KCNQ2/Q3channel opener has been approved by theEuropean Medicines Agency.So far, based on the structure-activity relationship of the traditionpotassium channel openers and analysis of retigabine, we synthesized99compounds.58of them are new chemical entities,32of them show potentialactivity as KCNQ2/Q3channel openers. Our previous studies point KG-9andJM-24has similar or equivalent activity with retigabine.In this study, according to our previous studies on the synthesis andscreening of KCNQ2/Q3channel openers, we used retigabine as positivecontrol agent and KG-9and JM-24as hit compounds. We designed andsynthesized derivatives in order to get lead compound with better activity.Part â… : Preparation of cyclohexanemethanamine by usingborohydride-catalyzed systemObjective: To investigate the optimum conditions for preparation ofcyclohexanemethanamine.Methods: By using sodium borohydride-catalyzed system and threecompounds as starting materials, the preparation of cyclohexanemethanaminewas studied. Cyclohexanone was chosed as the raw materials via Knoevenageland reduction reaction to synthesize the title compound. The determination ofdifferent catalysts,amounts of catalyst,temperatures and reduction agents were studied.Results: The optimization of sythesis of cyclohexanemethanamine wasgot. Cyclohexanone was chosed as the raw materials via Knoevenagel withequivalent diethylamine and reduction reaction to synthesize the titlecompound by NaBH4/I2.Conclusion: After the determination of different catalysts,amounts ofcatalyst,temperatures and reduction agents, the new synthetic pathway ofcyclohexanone under a optimized reaction condition gave rise to the titlecompound with a yield of83.6%. The production struction was confirmed byESI-MS. The process in this study has several advantages such as readyavailability of starting material,simplified operation,mild conditions and highproduction yield. Part â…¡: Study on structure-activity of urea derivatives as KCNQ2/Q3potassium channel openersObjective: By high throughput screening, design, and synthesis ofKG-9's derivatives, the structure-activity relationship was studied, in order toprovide chemical foundation of the research on urea KCNQ2/Q3potassiumchannel openers.Methods: Based on the similarity and diversity of molecule, the structureof KG-9was modified and reformed. The activities as KCNQ2/Q3openers ofall target compounds were tested by high-throughput screening method on thestable KCNQ2/Q3-transfected Chinese hamster ovary(CHO)cells, andevaluated by the values of EC50determined with atomic absorption of Rb+.Results: In this study, we designed the synthesis of urea compounds:1-benzyl-3(-tert-butyl)urea(KG-S-1)ï¼›1-benzyl-3-cyclohexylurea(KG-S-2)ï¼›cyclohexylmethyl benzylcarbamate(KG-S-3)ï¼›benzyl(cyclohexylmethyl) carbamate (KG-S-4)ï¼›1-benzyl-3-(cyclohexylmethyl)-1-methylurea(KG-S-5)ï¼›1-(cyclohexylmethyl)-3-phenylurea (KG-S-6)ï¼›1-benzyl-3-cycloheptylurea (KG-S-7)ï¼›1-benzyl-3-cyclopentylurea(KG-S-8)ï¼›1-benzyl-3-cyclohexylure(aKG-S-9)ï¼›1-cyclohexyl-3-phenylurea(KG-S-10). According our activity assay,5compounds, i.e. KG-S-6,KG-S-7, KG-S-8, KG-S-9and KG-S-10, have showed potential activity asKCNQ2/Q3openers.Conclusion: In this study, urea KCNQ2/Q3potassium channel openershave to fulfil with pharmacophore stipulated by the tradition potassiumchannel openers. When there are two atoms the hydrogen bond acceptor andthe aromatic ring as well as the hydrophobic group, the activity is optimal.Besides, NH is pharmacophore; fat ring is pharmacophore. When hydrophobicgroup is cyclohexyl, the activity is optimal. Part â…¢: Study on the Design, Synthesis and activity evaluation of amideKCNQ2/Q3potassium channel openersObjective: By high throughput screening, design, and synthesis ofJM-24's derivatives, the structure-activity relationship was studied. The aim isto find new chemical KCNQ openers in order to provide such hit compountsfor research and development of new anti-epileptic agents.Methods: Based on the similarity and diversity of molecule, the structureof JM-24was modified and reformatted. The activities as KCNQ2/Q3openersof all target compounds were tested by high-throughput screening method onthe stable KCNQ2/Q3-transfected Chinese hamster ovary (CHO) cells, andevaluated by the values of EC50that determined with atomic absorption ofRb+.Results: In this study, we designed the synthesis of amide compounds: N-(cyclohexylmethyl)-2-(naphthalen-1-yl) acetamide (JM-S-1)2-(4-chlorophenyl)-N-cyclohexylacetamide(JM-S-2)ï¼›N(-cyclohexylmethyl)-2-(3,4-dichlorophenyl)acetamide(JM-S-3)ï¼›2-(4-chloro-3-nitrophenyl)-N-(cyclohexylmethyl)acetamide(JM-S-4)ï¼›N-(cyclohexylmethyl)-2-(2,4-dichlorophenyl)acetamide(JM-S-5)ï¼›2-(4-chloro-2-fluorophenyl)-N-(cyclohexylmethyl) acetamide (JM-S-6)ï¼›2-[4-chloro-3-(trifluoromethoxy)phenyl]-N-(cyclohexylmethyl)acetamide(JM-S-7)ï¼›2-[4-chloro-2-(trifluoromethyl)phenyl]-N-(cyclohexylmethyl)acetamide(JM-S-8)ï¼›2-[4-chloro-3-(trifluoromethyl)phenyl]-N-(cyclohexylmethyl)acetamide (JM-S-9)ï¼› N-benzylcyclohexanecarboxamide (JM-S-10)ï¼›N-phenylcyclohexanecarboxamide (JM-S-11)ï¼›N-phenethylcyclohexanecarboxamide (JM-S-12)ï¼›4-chloro-N-(cyclohexylmethyl)benzamide(JM-S-13)ï¼›2-(4-chlorophenyl)-N-(2-cyclohexylethyl)acetamide(JM-S-14)ï¼›N-(cyclohexylmethyl)-4-(trifluoromethyl)cyclohexanecarboxamid(eJM-S-15).According our activityassay,8compounds, i.e. JM-S-1,JM-S-3,JM-S-4,JM-S-5,JM-S-6,JM-S-10,JM-S-14and JM-S-15, have showed potential activity as KCNQ2/Q3openers.6of them are new chemical entities, JM-S-15has better activity comparedwith JM-24and retigabine, JM-S-1and JM-S-10have similar activitycompared with JM-24.Conclusion: Basis on the structure of JM-24,15compounds weredesigned and synthesized as target products, biological activity tests showedthat some compounds exhibited potential KCNQ2/Q3potassium channelopening activity, one lead compound was found in this study.