| 1 | Development of fluorine-substituted NH_(2)-biphenyl-diarylpyrimidines as highly potent non-nucleoside reverse transcriptase inhibitors:Boosting the safety and metabolic stability显示文摘Our recent studies for nonnucleoside reverse transcriptase inhibitors identified a highly potent compound JK-4b against WT HIV-1(EC_(50)=1.0 nmol/L),but the poor metabolic stability in human liver microsomes(t_(1/2)=14.6 min)and insufficient selectivity(SI=2059)with high cytotoxicity(CC_(50)=2.08μmol/L)remained major issues associated with JK-4b.The present efforts were devoted to the introduction of fluorine into the biphenyl ring of JK-4b,leading to the discovery of a novel series of fluorine-substituted NH_(2)-biphenyl-diarylpyrimidines with noticeable inhibitory activity toward WT HIV-1 strain(EC_(50)=1.8–349 nmol/L).The best compound 5t in this collection(EC_(50)=1.8 nmol/L,CC_(50)=117μmol/L)was 32-fold in selectivity(SI=66,443)compared to JK-4b and showed remarkable potency toward clinically multiple mutant strains,such as L100I,K103N,E138K,and Y181C.The metabolic stability of 5t was also significantly improved(t_(1/2)=74.52 min),approximately 5-fold higher than JK-4b in human liver microsomes(t_(1/2)=14.6 min).Also,5t possessed good stability in both human and monkey plasma.No significant in vitro inhibition effect toward CYP enzyme and hERG was observed.The single-dose acute toxicity test did not induce mice death or obvious pathological damage.These findings pave the way for further development of 5t as a drug candidate. | Xin Jin Shuai Wang Limin Zhao Wenjuan Huang Yinxiang Zhang Christophe Pannecouque Erik De Clercq Ge Meng Huri Piao Fener Chen | 2023 | Acta Pharmaceutica Sinica B2023，13，3： | 1 |
| 2 | Synthesis and anticonvulsant activity of 7-benzylamino-4,5-dihydro-[1,2,4] triazolo[4,3-a] quinolines显示文摘A series of 7-substituted-benzylamino-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline derivatives was synthesized and evaluated for their anticonvulsant activity.The subcutaneous pentylenetetrazole test(sc-PTZ)demonstrated that the most effective compound in controlling the sc-PTZ induced seizure was 7-(3-bromine-benzylamino)-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline(4j)with an ED50 of 5.0 mg/kg and the PI of 20.7,which was also safer than the reference drugs.And the maximal electroshock test(MES)demonstrated that among these derivatives,7-(3-fluorobenzylamino)-4,5-dihydro-[1,2,4]trizolo[4,3-a]quinoline(4i),with an ED50 of 15.3 mg/kg and the PI of 7.2,was the safest in MES test.Furthermore,their neurotoxicities were measured by the rotarod neurotoxicity test,and the results showed that all derivatives possessed lower neurotoxicity. | Cui Xiangshu Guan Liping Li Hailan Piao Huri Quan Zheshan | 2007 | Progress in Natural Science:Materials International2007，17，9： | 1 |
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