Synthesis of

The OPG/RANKL/RANK pathway is a promising target for the design of therapeutic agents used in the treatment of osteoporosis. E09241 with an N-methylpyridine-chlorofuranformamide structural skeleton was previously identified to decrease bone loss and thus protect against osteoporosis in ovariectomize...
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Gespeichert in:

Autor*in:	Liu, Chao [verfasserIn] Li, Yining [verfasserIn] Sheng, Ren [verfasserIn] Han, Xiaowan [verfasserIn] Bao, Li [verfasserIn] Wang, Chenyin [verfasserIn] Wang, Weizhi [verfasserIn] Jiang, Xinhai [verfasserIn] Han, Jiangxue [verfasserIn] Lei, Lijuan [verfasserIn] Li, Ni [verfasserIn] Zhang, Jing [verfasserIn] Chen, Minghua [verfasserIn] Li, Yan [verfasserIn] Wu, Yexiang [verfasserIn] Li, Shunwang [verfasserIn] Ren, Yu [verfasserIn] Xu, Yanni [verfasserIn] Si, Shuyi [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2021

Schlagwörter:	Osteoporosis OPG RANKL Osteoclast Osteoblast

Übergeordnetes Werk:	Enthalten in: Bioorganic chemistry - San Diego, Calif. : Elsevier, 1971, 116
Übergeordnetes Werk:	volume:116

DOI / URN:	10.1016/j.bioorg.2021.105361

Katalog-ID:	ELV006777457

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520			\|a The OPG/RANKL/RANK pathway is a promising target for the design of therapeutic agents used in the treatment of osteoporosis. E09241 with an N-methylpyridine-chlorofuranformamide structural skeleton was previously identified to decrease bone loss and thus protect against osteoporosis in ovariectomized rats through increasing osteoprotegerin (OPG) expression. In this study, 36 derivatives of E09241 (3a) were prepared. The synthesis, up-regulation of OPG activities, SAR (structure–activity relationship), and cytotoxicity of these compounds are presented. Compounds with good up-regulating OPG activities could inhibit RANKL (the receptor activator of nuclear factor-kappa B ligand)-induced osteoclastogenesis in RAW264.7 cells. Particularly, compounds 3c and 3i1 significantly reduced NFATc1 and MMP-9 protein expression through inhibition of the NF-κB and MAPK pathways in RANKL induced RAW264.7 cells. In addition, compounds 3c and 3v significantly promoted osteoblast differentiation in MC3T3-E1 cells in osteogenic medium, and compounds 3c, 3v, and 3i1 obviously increased OPG protein expression and secretion in MC3T3-E1 cells. Furthermore, the pharmacokinetic profiles, acute toxicity, and hERG K+ channel effects of compounds 3a, 3c, 3e, 3v, and 3i1 were investigated. Taken together, these results indicate that N-methylpyridine-chlorofuranformamide analog 3i1 could serve as a promising lead for the development of new agents for treating osteoporosis.
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650		4	\|a Osteoclast
650		4	\|a Osteoblast
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700	1		\|a Sheng, Ren \|e verfasserin \|4 aut
700	1		\|a Han, Xiaowan \|e verfasserin \|4 aut
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700	1		\|a Zhang, Jing \|e verfasserin \|4 aut
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700	1		\|a Li, Yan \|e verfasserin \|4 aut
700	1		\|a Wu, Yexiang \|e verfasserin \|4 aut
700	1		\|a Li, Shunwang \|e verfasserin \|4 aut
700	1		\|a Ren, Yu \|e verfasserin \|4 aut
700	1		\|a Xu, Yanni \|e verfasserin \|4 aut
700	1		\|a Si, Shuyi \|e verfasserin \|4 aut
773	0	8	\|i Enthalten in \|t Bioorganic chemistry \|d San Diego, Calif. : Elsevier, 1971 \|g 116 \|h Online-Ressource \|w (DE-627)254631681 \|w (DE-600)1462232-4 \|w (DE-576)104193603 \|x 1090-2120 \|7 nnns
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Indexfelder

author_variant	c l cl y l yl r s rs x h xh l b lb c w cw w w ww x j xj j h jh l l ll n l nl j z jz m c mc y l yl y w yw s l sl y r yr y x yx s s ss
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publishDate	2021
allfields	10.1016/j.bioorg.2021.105361 doi (DE-627)ELV006777457 (ELSEVIER)S0045-2068(21)00738-0 DE-627 ger DE-627 rda eng 540 DE-600 35.50 bkl 35.70 bkl Liu, Chao verfasserin aut Synthesis of 2021 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier The OPG/RANKL/RANK pathway is a promising target for the design of therapeutic agents used in the treatment of osteoporosis. E09241 with an N-methylpyridine-chlorofuranformamide structural skeleton was previously identified to decrease bone loss and thus protect against osteoporosis in ovariectomized rats through increasing osteoprotegerin (OPG) expression. In this study, 36 derivatives of E09241 (3a) were prepared. The synthesis, up-regulation of OPG activities, SAR (structure–activity relationship), and cytotoxicity of these compounds are presented. Compounds with good up-regulating OPG activities could inhibit RANKL (the receptor activator of nuclear factor-kappa B ligand)-induced osteoclastogenesis in RAW264.7 cells. Particularly, compounds 3c and 3i1 significantly reduced NFATc1 and MMP-9 protein expression through inhibition of the NF-κB and MAPK pathways in RANKL induced RAW264.7 cells. In addition, compounds 3c and 3v significantly promoted osteoblast differentiation in MC3T3-E1 cells in osteogenic medium, and compounds 3c, 3v, and 3i1 obviously increased OPG protein expression and secretion in MC3T3-E1 cells. Furthermore, the pharmacokinetic profiles, acute toxicity, and hERG K+ channel effects of compounds 3a, 3c, 3e, 3v, and 3i1 were investigated. Taken together, these results indicate that N-methylpyridine-chlorofuranformamide analog 3i1 could serve as a promising lead for the development of new agents for treating osteoporosis. Osteoporosis OPG RANKL Osteoclast Osteoblast Li, Yining verfasserin aut Sheng, Ren verfasserin aut Han, Xiaowan verfasserin aut Bao, Li verfasserin aut Wang, Chenyin verfasserin aut Wang, Weizhi verfasserin aut Jiang, Xinhai verfasserin aut Han, Jiangxue verfasserin aut Lei, Lijuan verfasserin aut Li, Ni verfasserin aut Zhang, Jing verfasserin aut Chen, Minghua verfasserin aut Li, Yan verfasserin aut Wu, Yexiang verfasserin aut Li, Shunwang verfasserin aut Ren, Yu verfasserin aut Xu, Yanni verfasserin aut Si, Shuyi verfasserin aut Enthalten in Bioorganic chemistry San Diego, Calif. : Elsevier, 1971 116 Online-Ressource (DE-627)254631681 (DE-600)1462232-4 (DE-576)104193603 1090-2120 nnns volume:116 GBV_USEFLAG_U SYSFLAG_U GBV_ELV SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_150 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4393 35.50 Organische Chemie: Allgemeines 35.70 Biochemie: Allgemeines AR 116
spelling	10.1016/j.bioorg.2021.105361 doi (DE-627)ELV006777457 (ELSEVIER)S0045-2068(21)00738-0 DE-627 ger DE-627 rda eng 540 DE-600 35.50 bkl 35.70 bkl Liu, Chao verfasserin aut Synthesis of 2021 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier The OPG/RANKL/RANK pathway is a promising target for the design of therapeutic agents used in the treatment of osteoporosis. E09241 with an N-methylpyridine-chlorofuranformamide structural skeleton was previously identified to decrease bone loss and thus protect against osteoporosis in ovariectomized rats through increasing osteoprotegerin (OPG) expression. In this study, 36 derivatives of E09241 (3a) were prepared. The synthesis, up-regulation of OPG activities, SAR (structure–activity relationship), and cytotoxicity of these compounds are presented. Compounds with good up-regulating OPG activities could inhibit RANKL (the receptor activator of nuclear factor-kappa B ligand)-induced osteoclastogenesis in RAW264.7 cells. Particularly, compounds 3c and 3i1 significantly reduced NFATc1 and MMP-9 protein expression through inhibition of the NF-κB and MAPK pathways in RANKL induced RAW264.7 cells. In addition, compounds 3c and 3v significantly promoted osteoblast differentiation in MC3T3-E1 cells in osteogenic medium, and compounds 3c, 3v, and 3i1 obviously increased OPG protein expression and secretion in MC3T3-E1 cells. Furthermore, the pharmacokinetic profiles, acute toxicity, and hERG K+ channel effects of compounds 3a, 3c, 3e, 3v, and 3i1 were investigated. Taken together, these results indicate that N-methylpyridine-chlorofuranformamide analog 3i1 could serve as a promising lead for the development of new agents for treating osteoporosis. Osteoporosis OPG RANKL Osteoclast Osteoblast Li, Yining verfasserin aut Sheng, Ren verfasserin aut Han, Xiaowan verfasserin aut Bao, Li verfasserin aut Wang, Chenyin verfasserin aut Wang, Weizhi verfasserin aut Jiang, Xinhai verfasserin aut Han, Jiangxue verfasserin aut Lei, Lijuan verfasserin aut Li, Ni verfasserin aut Zhang, Jing verfasserin aut Chen, Minghua verfasserin aut Li, Yan verfasserin aut Wu, Yexiang verfasserin aut Li, Shunwang verfasserin aut Ren, Yu verfasserin aut Xu, Yanni verfasserin aut Si, Shuyi verfasserin aut Enthalten in Bioorganic chemistry San Diego, Calif. : Elsevier, 1971 116 Online-Ressource (DE-627)254631681 (DE-600)1462232-4 (DE-576)104193603 1090-2120 nnns volume:116 GBV_USEFLAG_U SYSFLAG_U GBV_ELV SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_150 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4393 35.50 Organische Chemie: Allgemeines 35.70 Biochemie: Allgemeines AR 116
allfields_unstemmed	10.1016/j.bioorg.2021.105361 doi (DE-627)ELV006777457 (ELSEVIER)S0045-2068(21)00738-0 DE-627 ger DE-627 rda eng 540 DE-600 35.50 bkl 35.70 bkl Liu, Chao verfasserin aut Synthesis of 2021 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier The OPG/RANKL/RANK pathway is a promising target for the design of therapeutic agents used in the treatment of osteoporosis. E09241 with an N-methylpyridine-chlorofuranformamide structural skeleton was previously identified to decrease bone loss and thus protect against osteoporosis in ovariectomized rats through increasing osteoprotegerin (OPG) expression. In this study, 36 derivatives of E09241 (3a) were prepared. The synthesis, up-regulation of OPG activities, SAR (structure–activity relationship), and cytotoxicity of these compounds are presented. Compounds with good up-regulating OPG activities could inhibit RANKL (the receptor activator of nuclear factor-kappa B ligand)-induced osteoclastogenesis in RAW264.7 cells. Particularly, compounds 3c and 3i1 significantly reduced NFATc1 and MMP-9 protein expression through inhibition of the NF-κB and MAPK pathways in RANKL induced RAW264.7 cells. In addition, compounds 3c and 3v significantly promoted osteoblast differentiation in MC3T3-E1 cells in osteogenic medium, and compounds 3c, 3v, and 3i1 obviously increased OPG protein expression and secretion in MC3T3-E1 cells. Furthermore, the pharmacokinetic profiles, acute toxicity, and hERG K+ channel effects of compounds 3a, 3c, 3e, 3v, and 3i1 were investigated. Taken together, these results indicate that N-methylpyridine-chlorofuranformamide analog 3i1 could serve as a promising lead for the development of new agents for treating osteoporosis. Osteoporosis OPG RANKL Osteoclast Osteoblast Li, Yining verfasserin aut Sheng, Ren verfasserin aut Han, Xiaowan verfasserin aut Bao, Li verfasserin aut Wang, Chenyin verfasserin aut Wang, Weizhi verfasserin aut Jiang, Xinhai verfasserin aut Han, Jiangxue verfasserin aut Lei, Lijuan verfasserin aut Li, Ni verfasserin aut Zhang, Jing verfasserin aut Chen, Minghua verfasserin aut Li, Yan verfasserin aut Wu, Yexiang verfasserin aut Li, Shunwang verfasserin aut Ren, Yu verfasserin aut Xu, Yanni verfasserin aut Si, Shuyi verfasserin aut Enthalten in Bioorganic chemistry San Diego, Calif. : Elsevier, 1971 116 Online-Ressource (DE-627)254631681 (DE-600)1462232-4 (DE-576)104193603 1090-2120 nnns volume:116 GBV_USEFLAG_U SYSFLAG_U GBV_ELV SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_150 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4393 35.50 Organische Chemie: Allgemeines 35.70 Biochemie: Allgemeines AR 116
allfieldsGer	10.1016/j.bioorg.2021.105361 doi (DE-627)ELV006777457 (ELSEVIER)S0045-2068(21)00738-0 DE-627 ger DE-627 rda eng 540 DE-600 35.50 bkl 35.70 bkl Liu, Chao verfasserin aut Synthesis of 2021 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier The OPG/RANKL/RANK pathway is a promising target for the design of therapeutic agents used in the treatment of osteoporosis. E09241 with an N-methylpyridine-chlorofuranformamide structural skeleton was previously identified to decrease bone loss and thus protect against osteoporosis in ovariectomized rats through increasing osteoprotegerin (OPG) expression. In this study, 36 derivatives of E09241 (3a) were prepared. The synthesis, up-regulation of OPG activities, SAR (structure–activity relationship), and cytotoxicity of these compounds are presented. Compounds with good up-regulating OPG activities could inhibit RANKL (the receptor activator of nuclear factor-kappa B ligand)-induced osteoclastogenesis in RAW264.7 cells. Particularly, compounds 3c and 3i1 significantly reduced NFATc1 and MMP-9 protein expression through inhibition of the NF-κB and MAPK pathways in RANKL induced RAW264.7 cells. In addition, compounds 3c and 3v significantly promoted osteoblast differentiation in MC3T3-E1 cells in osteogenic medium, and compounds 3c, 3v, and 3i1 obviously increased OPG protein expression and secretion in MC3T3-E1 cells. Furthermore, the pharmacokinetic profiles, acute toxicity, and hERG K+ channel effects of compounds 3a, 3c, 3e, 3v, and 3i1 were investigated. Taken together, these results indicate that N-methylpyridine-chlorofuranformamide analog 3i1 could serve as a promising lead for the development of new agents for treating osteoporosis. Osteoporosis OPG RANKL Osteoclast Osteoblast Li, Yining verfasserin aut Sheng, Ren verfasserin aut Han, Xiaowan verfasserin aut Bao, Li verfasserin aut Wang, Chenyin verfasserin aut Wang, Weizhi verfasserin aut Jiang, Xinhai verfasserin aut Han, Jiangxue verfasserin aut Lei, Lijuan verfasserin aut Li, Ni verfasserin aut Zhang, Jing verfasserin aut Chen, Minghua verfasserin aut Li, Yan verfasserin aut Wu, Yexiang verfasserin aut Li, Shunwang verfasserin aut Ren, Yu verfasserin aut Xu, Yanni verfasserin aut Si, Shuyi verfasserin aut Enthalten in Bioorganic chemistry San Diego, Calif. : Elsevier, 1971 116 Online-Ressource (DE-627)254631681 (DE-600)1462232-4 (DE-576)104193603 1090-2120 nnns volume:116 GBV_USEFLAG_U SYSFLAG_U GBV_ELV SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_150 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4393 35.50 Organische Chemie: Allgemeines 35.70 Biochemie: Allgemeines AR 116
allfieldsSound	10.1016/j.bioorg.2021.105361 doi (DE-627)ELV006777457 (ELSEVIER)S0045-2068(21)00738-0 DE-627 ger DE-627 rda eng 540 DE-600 35.50 bkl 35.70 bkl Liu, Chao verfasserin aut Synthesis of 2021 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier The OPG/RANKL/RANK pathway is a promising target for the design of therapeutic agents used in the treatment of osteoporosis. E09241 with an N-methylpyridine-chlorofuranformamide structural skeleton was previously identified to decrease bone loss and thus protect against osteoporosis in ovariectomized rats through increasing osteoprotegerin (OPG) expression. In this study, 36 derivatives of E09241 (3a) were prepared. The synthesis, up-regulation of OPG activities, SAR (structure–activity relationship), and cytotoxicity of these compounds are presented. Compounds with good up-regulating OPG activities could inhibit RANKL (the receptor activator of nuclear factor-kappa B ligand)-induced osteoclastogenesis in RAW264.7 cells. Particularly, compounds 3c and 3i1 significantly reduced NFATc1 and MMP-9 protein expression through inhibition of the NF-κB and MAPK pathways in RANKL induced RAW264.7 cells. In addition, compounds 3c and 3v significantly promoted osteoblast differentiation in MC3T3-E1 cells in osteogenic medium, and compounds 3c, 3v, and 3i1 obviously increased OPG protein expression and secretion in MC3T3-E1 cells. Furthermore, the pharmacokinetic profiles, acute toxicity, and hERG K+ channel effects of compounds 3a, 3c, 3e, 3v, and 3i1 were investigated. Taken together, these results indicate that N-methylpyridine-chlorofuranformamide analog 3i1 could serve as a promising lead for the development of new agents for treating osteoporosis. Osteoporosis OPG RANKL Osteoclast Osteoblast Li, Yining verfasserin aut Sheng, Ren verfasserin aut Han, Xiaowan verfasserin aut Bao, Li verfasserin aut Wang, Chenyin verfasserin aut Wang, Weizhi verfasserin aut Jiang, Xinhai verfasserin aut Han, Jiangxue verfasserin aut Lei, Lijuan verfasserin aut Li, Ni verfasserin aut Zhang, Jing verfasserin aut Chen, Minghua verfasserin aut Li, Yan verfasserin aut Wu, Yexiang verfasserin aut Li, Shunwang verfasserin aut Ren, Yu verfasserin aut Xu, Yanni verfasserin aut Si, Shuyi verfasserin aut Enthalten in Bioorganic chemistry San Diego, Calif. : Elsevier, 1971 116 Online-Ressource (DE-627)254631681 (DE-600)1462232-4 (DE-576)104193603 1090-2120 nnns volume:116 GBV_USEFLAG_U SYSFLAG_U GBV_ELV SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_150 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4393 35.50 Organische Chemie: Allgemeines 35.70 Biochemie: Allgemeines AR 116
language	English
source	Enthalten in Bioorganic chemistry 116 volume:116
sourceStr	Enthalten in Bioorganic chemistry 116 volume:116
format_phy_str_mv	Article
bklname	Organische Chemie: Allgemeines Biochemie: Allgemeines
institution	findex.gbv.de
topic_facet	Osteoporosis OPG RANKL Osteoclast Osteoblast
dewey-raw	540
isfreeaccess_bool	false
container_title	Bioorganic chemistry
authorswithroles_txt_mv	Liu, Chao @@aut@@ Li, Yining @@aut@@ Sheng, Ren @@aut@@ Han, Xiaowan @@aut@@ Bao, Li @@aut@@ Wang, Chenyin @@aut@@ Wang, Weizhi @@aut@@ Jiang, Xinhai @@aut@@ Han, Jiangxue @@aut@@ Lei, Lijuan @@aut@@ Li, Ni @@aut@@ Zhang, Jing @@aut@@ Chen, Minghua @@aut@@ Li, Yan @@aut@@ Wu, Yexiang @@aut@@ Li, Shunwang @@aut@@ Ren, Yu @@aut@@ Xu, Yanni @@aut@@ Si, Shuyi @@aut@@
publishDateDaySort_date	2021-01-01T00:00:00Z
hierarchy_top_id	254631681
dewey-sort	3540
id	ELV006777457
language_de	englisch
fullrecord	<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a22002652 4500</leader><controlfield tag="001">ELV006777457</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230524145429.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">230506s2021 xx \|\|\|\|\|o 00\| \|\|eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.1016/j.bioorg.2021.105361</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)ELV006777457</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(ELSEVIER)S0045-2068(21)00738-0</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rda</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="082" ind1="0" ind2="4"><subfield code="a">540</subfield><subfield code="q">DE-600</subfield></datafield><datafield tag="084" ind1=" " ind2=" "><subfield code="a">35.50</subfield><subfield code="2">bkl</subfield></datafield><datafield tag="084" ind1=" " ind2=" "><subfield code="a">35.70</subfield><subfield code="2">bkl</subfield></datafield><datafield tag="100" ind1="1" ind2=" "><subfield code="a">Liu, Chao</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Synthesis of</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2021</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">nicht spezifiziert</subfield><subfield code="b">zzz</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">The OPG/RANKL/RANK pathway is a promising target for the design of therapeutic agents used in the treatment of osteoporosis. E09241 with an N-methylpyridine-chlorofuranformamide structural skeleton was previously identified to decrease bone loss and thus protect against osteoporosis in ovariectomized rats through increasing osteoprotegerin (OPG) expression. In this study, 36 derivatives of E09241 (3a) were prepared. The synthesis, up-regulation of OPG activities, SAR (structure–activity relationship), and cytotoxicity of these compounds are presented. Compounds with good up-regulating OPG activities could inhibit RANKL (the receptor activator of nuclear factor-kappa B ligand)-induced osteoclastogenesis in RAW264.7 cells. Particularly, compounds 3c and 3i1 significantly reduced NFATc1 and MMP-9 protein expression through inhibition of the NF-κB and MAPK pathways in RANKL induced RAW264.7 cells. In addition, compounds 3c and 3v significantly promoted osteoblast differentiation in MC3T3-E1 cells in osteogenic medium, and compounds 3c, 3v, and 3i1 obviously increased OPG protein expression and secretion in MC3T3-E1 cells. Furthermore, the pharmacokinetic profiles, acute toxicity, and hERG K+ channel effects of compounds 3a, 3c, 3e, 3v, and 3i1 were investigated. 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author	Liu, Chao
spellingShingle	Liu, Chao ddc 540 bkl 35.50 bkl 35.70 misc Osteoporosis misc OPG misc RANKL misc Osteoclast misc Osteoblast Synthesis of
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topic_title	540 DE-600 35.50 bkl 35.70 bkl Synthesis of Osteoporosis OPG RANKL Osteoclast Osteoblast
topic	ddc 540 bkl 35.50 bkl 35.70 misc Osteoporosis misc OPG misc RANKL misc Osteoclast misc Osteoblast
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title	Synthesis of
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title_full	Synthesis of
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author_browse	Liu, Chao Li, Yining Sheng, Ren Han, Xiaowan Bao, Li Wang, Chenyin Wang, Weizhi Jiang, Xinhai Han, Jiangxue Lei, Lijuan Li, Ni Zhang, Jing Chen, Minghua Li, Yan Wu, Yexiang Li, Shunwang Ren, Yu Xu, Yanni Si, Shuyi
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title_sort	synthesis of
title_auth	Synthesis of
abstract	The OPG/RANKL/RANK pathway is a promising target for the design of therapeutic agents used in the treatment of osteoporosis. E09241 with an N-methylpyridine-chlorofuranformamide structural skeleton was previously identified to decrease bone loss and thus protect against osteoporosis in ovariectomized rats through increasing osteoprotegerin (OPG) expression. In this study, 36 derivatives of E09241 (3a) were prepared. The synthesis, up-regulation of OPG activities, SAR (structure–activity relationship), and cytotoxicity of these compounds are presented. Compounds with good up-regulating OPG activities could inhibit RANKL (the receptor activator of nuclear factor-kappa B ligand)-induced osteoclastogenesis in RAW264.7 cells. Particularly, compounds 3c and 3i1 significantly reduced NFATc1 and MMP-9 protein expression through inhibition of the NF-κB and MAPK pathways in RANKL induced RAW264.7 cells. In addition, compounds 3c and 3v significantly promoted osteoblast differentiation in MC3T3-E1 cells in osteogenic medium, and compounds 3c, 3v, and 3i1 obviously increased OPG protein expression and secretion in MC3T3-E1 cells. Furthermore, the pharmacokinetic profiles, acute toxicity, and hERG K+ channel effects of compounds 3a, 3c, 3e, 3v, and 3i1 were investigated. Taken together, these results indicate that N-methylpyridine-chlorofuranformamide analog 3i1 could serve as a promising lead for the development of new agents for treating osteoporosis.
abstractGer	The OPG/RANKL/RANK pathway is a promising target for the design of therapeutic agents used in the treatment of osteoporosis. E09241 with an N-methylpyridine-chlorofuranformamide structural skeleton was previously identified to decrease bone loss and thus protect against osteoporosis in ovariectomized rats through increasing osteoprotegerin (OPG) expression. In this study, 36 derivatives of E09241 (3a) were prepared. The synthesis, up-regulation of OPG activities, SAR (structure–activity relationship), and cytotoxicity of these compounds are presented. Compounds with good up-regulating OPG activities could inhibit RANKL (the receptor activator of nuclear factor-kappa B ligand)-induced osteoclastogenesis in RAW264.7 cells. Particularly, compounds 3c and 3i1 significantly reduced NFATc1 and MMP-9 protein expression through inhibition of the NF-κB and MAPK pathways in RANKL induced RAW264.7 cells. In addition, compounds 3c and 3v significantly promoted osteoblast differentiation in MC3T3-E1 cells in osteogenic medium, and compounds 3c, 3v, and 3i1 obviously increased OPG protein expression and secretion in MC3T3-E1 cells. Furthermore, the pharmacokinetic profiles, acute toxicity, and hERG K+ channel effects of compounds 3a, 3c, 3e, 3v, and 3i1 were investigated. Taken together, these results indicate that N-methylpyridine-chlorofuranformamide analog 3i1 could serve as a promising lead for the development of new agents for treating osteoporosis.
abstract_unstemmed	The OPG/RANKL/RANK pathway is a promising target for the design of therapeutic agents used in the treatment of osteoporosis. E09241 with an N-methylpyridine-chlorofuranformamide structural skeleton was previously identified to decrease bone loss and thus protect against osteoporosis in ovariectomized rats through increasing osteoprotegerin (OPG) expression. In this study, 36 derivatives of E09241 (3a) were prepared. The synthesis, up-regulation of OPG activities, SAR (structure–activity relationship), and cytotoxicity of these compounds are presented. Compounds with good up-regulating OPG activities could inhibit RANKL (the receptor activator of nuclear factor-kappa B ligand)-induced osteoclastogenesis in RAW264.7 cells. Particularly, compounds 3c and 3i1 significantly reduced NFATc1 and MMP-9 protein expression through inhibition of the NF-κB and MAPK pathways in RANKL induced RAW264.7 cells. In addition, compounds 3c and 3v significantly promoted osteoblast differentiation in MC3T3-E1 cells in osteogenic medium, and compounds 3c, 3v, and 3i1 obviously increased OPG protein expression and secretion in MC3T3-E1 cells. Furthermore, the pharmacokinetic profiles, acute toxicity, and hERG K+ channel effects of compounds 3a, 3c, 3e, 3v, and 3i1 were investigated. Taken together, these results indicate that N-methylpyridine-chlorofuranformamide analog 3i1 could serve as a promising lead for the development of new agents for treating osteoporosis.
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title_short	Synthesis of
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author2	Li, Yining Sheng, Ren Han, Xiaowan Bao, Li Wang, Chenyin Wang, Weizhi Jiang, Xinhai Han, Jiangxue Lei, Lijuan Li, Ni Zhang, Jing Chen, Minghua Li, Yan Wu, Yexiang Li, Shunwang Ren, Yu Xu, Yanni Si, Shuyi
author2Str	Li, Yining Sheng, Ren Han, Xiaowan Bao, Li Wang, Chenyin Wang, Weizhi Jiang, Xinhai Han, Jiangxue Lei, Lijuan Li, Ni Zhang, Jing Chen, Minghua Li, Yan Wu, Yexiang Li, Shunwang Ren, Yu Xu, Yanni Si, Shuyi
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up_date	2024-07-06T22:31:41.022Z
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E09241 with an N-methylpyridine-chlorofuranformamide structural skeleton was previously identified to decrease bone loss and thus protect against osteoporosis in ovariectomized rats through increasing osteoprotegerin (OPG) expression. In this study, 36 derivatives of E09241 (3a) were prepared. The synthesis, up-regulation of OPG activities, SAR (structure–activity relationship), and cytotoxicity of these compounds are presented. Compounds with good up-regulating OPG activities could inhibit RANKL (the receptor activator of nuclear factor-kappa B ligand)-induced osteoclastogenesis in RAW264.7 cells. Particularly, compounds 3c and 3i1 significantly reduced NFATc1 and MMP-9 protein expression through inhibition of the NF-κB and MAPK pathways in RANKL induced RAW264.7 cells. In addition, compounds 3c and 3v significantly promoted osteoblast differentiation in MC3T3-E1 cells in osteogenic medium, and compounds 3c, 3v, and 3i1 obviously increased OPG protein expression and secretion in MC3T3-E1 cells. Furthermore, the pharmacokinetic profiles, acute toxicity, and hERG K+ channel effects of compounds 3a, 3c, 3e, 3v, and 3i1 were investigated. Taken together, these results indicate that N-methylpyridine-chlorofuranformamide analog 3i1 could serve as a promising lead for the development of new agents for treating osteoporosis.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Osteoporosis</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">OPG</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">RANKL</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Osteoclast</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Osteoblast</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Li, Yining</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Sheng, Ren</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield 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