Substituted benzothiophene or benzofuran derivatives as a novel class of bone morphogenetic protein-2 up-regulators: synthesis, structure-activity relationships, and preventive bone loss efficacies in senescence accelerated mice (SAMP6) and ovariectomized rats.
In this work, substituted benzothiophene and benzofuran compounds were found to be a new class of potential anabolic agents by enhancing BMP-2 expression. A series of benzothiophene and benzofuran derivatives have been synthesized, and their activities of up-regulating BMP-2 and bone loss prevention efficacies in SAMP6 mice and OVX rats have been studied. Benzothiophenes 1, 3, 14, 4a, 7a, 8a, and benzofuran analogue 2 showed higher BMP-2 up-regulation rates in vitro. Compound 8a was found to significantly affect the bone formation rate of tested SAMP6 mice. Compound 1 showed an improved bone quality in SAMP6 mice and also showed activity in OVX rats. We have demonstrated that substituted benzothiophene and benzofuran derivatives, especially compounds 1 and 8a, enhance BMP-2 expression in vitro and in vivo and stimulate bone formation and trabecular connectivity restoration in vivo. The compounds represent potential leads in the development of a new class of anabolic agents.
Guo
Hui-Fang
HF
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China.
Shao
Hua-Yi
HY
Yang
Zhao-Yong
ZY
Xue
Si-Tu
ST
Li
Xue
X
Liu
Zong-Ying
ZY
He
Xiao-Bo
XB
Jiang
Jian-Dong
JD
Zhang
Yue-Qin
YQ
Si
Shu-Yi
SY
Li
Zhuo-Rong
ZR
D045930:Anabolic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001572:Benzofurans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015519:Bone Density / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D055396:Bone Morphogenetic Protein 2 / Q000096:biosynthesis*; D002460:Cell Line; D005260:Female; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D010024:Osteoporosis / Q000517:prevention & control*; D010052:Ovariectomy; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015854:Up-Regulation
D045930:Anabolic Agents; D001572:Benzofurans; D050071:Bone Density Conservation Agents; D055396:Bone Morphogenetic Protein 2; D013876:Thiophenes