BVT 2733

BVT 2733 is a novel, small-molecule, nonsteroidal, isoform-selective inhibitor of 11beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) with IC50 of 96 nM (mice)^[1].

BVT 2733 attenuated the mRNA levels of MCP-1 and IL-6 in PA or LPS treated J774A.1 macrophages. The protein levels of MCP-1 and IL-6 in the medium were also attenuated^[2]. After constructing the mouse 11β-HSD1 overexpression lentiviral vector, MC3T3-E1 preosteoblasts were infected with negative control lentivirus and overexpressing 11β-HSD1 lentivirus, respectively, and then added with the selective inhibitor of 11β-HSD1 BVT 2733 to reverse the inhibitory effect of 11β-HSD1 expression on osteogenesis^[6]. A significant increase in the expression of BAT-specific genes, including UCP1, Cidea, Cox7a1 and Cox8b, was observed in BVT 2733 treated and 11β-HSD1-deficient mouse native brown adipocytes^[7].

BVT 2733 administration normalized the expression profile of adiponkines by up-regulating the mRNA levels of adiponectin and vaspin and down-regulating the expression of resistin in adipose tissue. In line with these changes in adipose tissue serum levels of adiponectin and leptin were also improved by BVT 2733 treatment^[2]. BVT 2733 treatment attenuated the arthritis severity and anti-CII level in CIA mice. BVT-2733 also decreased the levels of serum TNF-α, IL-1β, IL-6 and IL-17. BVT 2733 treatment also significantly reduced synovial inflammation and joint destruction^[3]. In hyperglycemic, but not in normal mice, BVT 2733 lowered circulating glucose and insulin levels. In oral glucose tolerance tests in ob/ob and KKAy mice, glucose concentrations were 65-75% of vehicle values after BVT 2733 treatment, and in KKAy mice insulin concentrations were decreased^[4]. BVT 2733 reduced food intake but prevented a concomitant reduction in lean body mass and energy expenditure. The latter effects may have contributed to improved glucose tolerance^[5].

References:
[1]: Alberts P, Engblom L, et,al. Selective inhibition of 11beta-hydroxysteroid dehydrogenase type 1 decreases blood glucose concentrations in hyperglycaemic mice. Diabetologia. 2002 Nov;45(11):1528-32. doi: 10.1007/s00125-002-0959-6. Epub 2002 Sep 18. PMID: 12436336.
[2]: Wang L, Liu J, et,al. BVT.2733, a selective 11β-hydroxysteroid dehydrogenase type 1 inhibitor, attenuates obesity and inflammation in diet-induced obese mice. PLoS One. 2012;7(7):e40056. doi: 10.1371/journal.pone.0040056. Epub 2012 Jul 2. PMID: 22768329; PMCID: PMC3388048.
[3]: Zhang L, Dong Y, et,al. 11β-Hydroxysteroid dehydrogenase 1 inhibition attenuates collagen-induced arthritis. Int Immunopharmacol. 2013 Nov;17(3):489-94. doi: 10.1016/j.intimp.2013.07.015. Epub 2013 Aug 11. PMID: 23938253.
[4]: Alberts P, Nilsson C, et,al. Selective inhibition of 11 beta-hydroxysteroid dehydrogenase type 1 improves hepatic insulin sensitivity in hyperglycemic mice strains. Endocrinology. 2003 Nov;144(11):4755-62. doi: 10.1210/en.2003-0344. Epub 2003 Jul 31. PMID: 12960099.
[5]: Wang SJ, Birtles S, et,al. Inhibition of 11beta-hydroxysteroid dehydrogenase type 1 reduces food intake and weight gain but maintains energy expenditure in diet-induced obese mice. Diabetologia. 2006 Jun;49(6):1333-7. doi: 10.1007/s00125-006-0239-y. Epub 2006 Apr 13. PMID: 16612591.
[6]: Wu L, Qi H, et,al. 11β-Hydroxysteroid dehydrogenase type 1 selective inhibitor BVT.2733 protects osteoblasts against endogenous glucocorticoid induced dysfunction. Endocr J. 2013;60(9):1047-58. doi: 10.1507/endocrj.ej12-0376. Epub 2013 Jun 12. PMID: 23759754.
[7]: Liu J, Kong X, et,al. Essential roles of 11β-HSD1 in regulating brown adipocyte function. J Mol Endocrinol. 2013 Jan 11;50(1):103-13. doi: 10.1530/JME-12-0099. PMID: 23197361.