A series of 2,4,5-triaryl substituted 1H-pyrazol-3（2H）-ones,as ALK5 inhibitors,were desigened,synthesized and evaluated in vitro.Most compounds exhibited noticeable ALK5 inhibition activities at 1μmol/L and display...A series of 2,4,5-triaryl substituted 1H-pyrazol-3（2H）-ones,as ALK5 inhibitors,were desigened,synthesized and evaluated in vitro.Most compounds exhibited noticeable ALK5 inhibition activities at 1μmol/L and displayed no significant cytotoxicities at 30μmol/L.展开更多
Ten new 1, 5-diarulpyrazole-3-carboxamide compounds were synthesized and their structures were identified by ^1H-NMR and FAB-MS. The primary biological tests showed that compound 4j exhibited some ALK5 inhibitory acti...Ten new 1, 5-diarulpyrazole-3-carboxamide compounds were synthesized and their structures were identified by ^1H-NMR and FAB-MS. The primary biological tests showed that compound 4j exhibited some ALK5 inhibitory activity at concentration of 1μmol/L.展开更多
The transforming growth factor-β （TGF-β） plays a crucial role in the beginning andprogression of fibrosis in various organ systems such as lung, heart, liver and kidney. TGF-fl type Ireceptor kinase （activin rece...The transforming growth factor-β （TGF-β） plays a crucial role in the beginning andprogression of fibrosis in various organ systems such as lung, heart, liver and kidney. TGF-fl type Ireceptor kinase （activin receptor-like kinase 5, ALK5） inhibitors might have potential activity forthe treatment of relevant diseases. In this paper, the three-dimensional quantitativestructure-activity relationship （3D-QSAR） including comparative molecular field analysis （CoMFA）and comparative molecular similarity indices analysis （CoMSIA） were used to analyze thestructural requirements based on a dataset of 123 4-（[1,2,4]Triazolo[1,5-a]pyridine-6-yl）-5（3）-（6-methylpyridin-2-yl）imidazole analogues which acted as ALK5 inhibitors. The obtainedCoMFA model （q2= 0.652, r2= 0.876, r2pred = 0.845） and CoMSIA model （q^2= 0.648, r^2= 0.884,r^2pred = 0.853） were robust and satisfactory. The predictive ability of the derived models wasvalidated using a test set of 28 compounds. Additionally, potentially important structural featuresrequired to enhance activity were also elucidated by the contour maps derived from CoMFA andCoMSIA models. The results will be helpful to guide drug design strategies aimed at obtainingpotent and selective ALK5 inhibitors.展开更多
转化生长因子-β(TGF-β)在许多疾病中过表达,是治疗肿瘤的重要靶点.合成了2个系列3-取代-5-((5-(6-甲基吡啶-2-酰基)-4-(喹啉-6-基)-1氢-咪唑-2-基)亚甲基)-2-噁唑烷-4-酮化合物(12、13a~13e和14a~14h),并对其进行了活性受体样激酶5(AL...转化生长因子-β(TGF-β)在许多疾病中过表达,是治疗肿瘤的重要靶点.合成了2个系列3-取代-5-((5-(6-甲基吡啶-2-酰基)-4-(喹啉-6-基)-1氢-咪唑-2-基)亚甲基)-2-噁唑烷-4-酮化合物(12、13a~13e和14a~14h),并对其进行了活性受体样激酶5(ALK5)抑制活性评价.其中(Z)-6-(5-((5-(6-甲基吡啶-2-基)-4-(喹喔啉-6-基)-1H-咪唑-2-基)亚甲基)-4-羰基-2-硫代羰基噻唑-3-基)己酸(13e)对ALK5激酶的活性最高(IC_(50)=0.451μmol·L^(-1)),对p38α激酶的选择性指数大于22,比临床候选化合物LY-2157299选择性高5.0倍.在TGF-β抑制剂的研究中发现这些罗丹宁化合物具有良好的抗真菌活性,而且对革兰氏阳性菌和革兰氏阴性菌显示很高的选择性.它们显示与阳性对照化合物氟康唑(MIC=1μg/mL)类似或更高的抗真菌活性(MIC=0.5 or 1μg/mL).展开更多
文摘A series of 2,4,5-triaryl substituted 1H-pyrazol-3（2H）-ones,as ALK5 inhibitors,were desigened,synthesized and evaluated in vitro.Most compounds exhibited noticeable ALK5 inhibition activities at 1μmol/L and displayed no significant cytotoxicities at 30μmol/L.
文摘Ten new 1, 5-diarulpyrazole-3-carboxamide compounds were synthesized and their structures were identified by ^1H-NMR and FAB-MS. The primary biological tests showed that compound 4j exhibited some ALK5 inhibitory activity at concentration of 1μmol/L.
基金supported by the Collaborative Innovation Center Project of Shanxi 'Astragalus' Resource Industrialization and Industrial Internationalization(No.HQXTCXZX2016-021)Natural Science Foundation of Shanxi Province(No.201601D011112)
文摘The transforming growth factor-β （TGF-β） plays a crucial role in the beginning andprogression of fibrosis in various organ systems such as lung, heart, liver and kidney. TGF-fl type Ireceptor kinase （activin receptor-like kinase 5, ALK5） inhibitors might have potential activity forthe treatment of relevant diseases. In this paper, the three-dimensional quantitativestructure-activity relationship （3D-QSAR） including comparative molecular field analysis （CoMFA）and comparative molecular similarity indices analysis （CoMSIA） were used to analyze thestructural requirements based on a dataset of 123 4-（[1,2,4]Triazolo[1,5-a]pyridine-6-yl）-5（3）-（6-methylpyridin-2-yl）imidazole analogues which acted as ALK5 inhibitors. The obtainedCoMFA model （q2= 0.652, r2= 0.876, r2pred = 0.845） and CoMSIA model （q^2= 0.648, r^2= 0.884,r^2pred = 0.853） were robust and satisfactory. The predictive ability of the derived models wasvalidated using a test set of 28 compounds. Additionally, potentially important structural featuresrequired to enhance activity were also elucidated by the contour maps derived from CoMFA andCoMSIA models. The results will be helpful to guide drug design strategies aimed at obtainingpotent and selective ALK5 inhibitors.
文摘转化生长因子-β(TGF-β)在许多疾病中过表达,是治疗肿瘤的重要靶点.合成了2个系列3-取代-5-((5-(6-甲基吡啶-2-酰基)-4-(喹啉-6-基)-1氢-咪唑-2-基)亚甲基)-2-噁唑烷-4-酮化合物(12、13a~13e和14a~14h),并对其进行了活性受体样激酶5(ALK5)抑制活性评价.其中(Z)-6-(5-((5-(6-甲基吡啶-2-基)-4-(喹喔啉-6-基)-1H-咪唑-2-基)亚甲基)-4-羰基-2-硫代羰基噻唑-3-基)己酸(13e)对ALK5激酶的活性最高(IC_(50)=0.451μmol·L^(-1)),对p38α激酶的选择性指数大于22,比临床候选化合物LY-2157299选择性高5.0倍.在TGF-β抑制剂的研究中发现这些罗丹宁化合物具有良好的抗真菌活性,而且对革兰氏阳性菌和革兰氏阴性菌显示很高的选择性.它们显示与阳性对照化合物氟康唑(MIC=1μg/mL)类似或更高的抗真菌活性(MIC=0.5 or 1μg/mL).
