Identification of Novel 2-((1-(Benzyl(2-hydroxy-2-phenylethyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamoyl)benzoic Acid Analogues as BMP-2 Stimulators

被引：15

作者：

Balaramnavar, Vishal M. ^{[1
]}

Khan, Imran A. ^{[1
]}

Siddiqui, Jawed Akhtar ^{[2
]}

Khan, Mohd Parvez ^{[2
]}

Chakravarti, Bandana ^{[2
]}

Sharan, Kunal ^{[2
]}

Swarnkar, Gaurav ^{[2
]}

Rastogi, Namrata ^{[2
]}

Siddiqui, H. H. ^{[3
]}

Mishra, Durga Prasad ^{[2
]}

Chattopadhyay, Naibedya ^{[2
]}

Saxena, Anil K. ^{[1
]}

机构：

[1] Cent Drug Res Inst, CSIR, Div Med & Proc Chem, Lucknow 226001, Uttar Pradesh, India

[2] Cent Drug Res Inst, CSIR, Div Endocrinol, Lucknow 226001, Uttar Pradesh, India

[3] Integral Univ, Dept Pharm, Lucknow, Uttar Pradesh, India

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 55卷 / 19期

关键词：

BONE MORPHOGENETIC PROTEIN-2; FORMATION IN-VITRO; DRILL-HOLE INJURY; OSTEOBLAST DIFFERENTIATION; ANABOLIC AGENTS; CELLS; EXPRESSION; MINERALIZATION; OSTEOPOROSIS; DERIVATIVES;

D O I：

10.1021/jm300985d

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The synthesis and SAR studies of 10 new chemical entities (NCEs) that have shown BMP-2 stimulation and osteoblast differentiation are reported. Among these, 2-((1-(benzyl(2-hydroxy-2-phenylethyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamoyl)benzoic acid (11) was the most effective while its analogue 13 also showed good activity in inducing osteoblast BMP-2 production. Compound 11 induced osteoblast differentiation in vitro, and this effect was abrogated by a physiological BMP-2 inhibitor, noggin. It also exhibited dose dependent increase in nascent bone formation (2.16- and 3.12-fold more than the control at 1 and 5 mg/kg dose, respectively) at the fracture site in rats. At the maximum osteogenic concentration, compound 11 significantly inhibited osteoblastic proteosomal activity. This compound was safe, as it had no effect on BMP synthesis in cardiovascular tissue.

引用

页码：8248 / 8259

页数：12

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