TY - JOUR
T1 - Adamantyl carboxamides and acetamides as potent human 11β- hydroxysteroid dehydrogenase type 1 inhibitors
AU - Su, Xiangdong
AU - Halem, Heather A.
AU - Thomas, Mark P.
AU - Moutrille, Cecille
AU - Culler, Michael D.
AU - Vicker, Nigel
AU - Potter, Barry V. L.
PY - 2012/11/1
Y1 - 2012/11/1
N2 - The modulation of 11β-HSD1 activity with selective inhibitors has beneficial effects on various metabolic disorders including insulin resistance, dyslipidemia and obesity. Here we report the discovery of a series of novel adamantyl carboxamide and acetamide derivatives as selective inhibitors of human 11β-HSD1 in HEK-293 cells transfected with the HSD11B1 gene. Optimization based on an initially identified 11β-HSD1 inhibitor (3) led to the discovery of potent inhibitors with IC 50 values in the 100 nM range. These compounds are also highly selective 11β-HSD1 inhibitors with no activity against 11β-HSD2 and 17β-HSD1. Compound 15 (IC 50 = 114 nM) with weak inhibitory activity against the key human cytochrome P450 enzymes and moderate stability in incubation with human liver microsomes is worthy of further development. Importantly, compound 41 (IC 50 = 280 nM) provides a new lead that incorporates an adamantyl group surrogate and should enable further series diversification.
AB - The modulation of 11β-HSD1 activity with selective inhibitors has beneficial effects on various metabolic disorders including insulin resistance, dyslipidemia and obesity. Here we report the discovery of a series of novel adamantyl carboxamide and acetamide derivatives as selective inhibitors of human 11β-HSD1 in HEK-293 cells transfected with the HSD11B1 gene. Optimization based on an initially identified 11β-HSD1 inhibitor (3) led to the discovery of potent inhibitors with IC 50 values in the 100 nM range. These compounds are also highly selective 11β-HSD1 inhibitors with no activity against 11β-HSD2 and 17β-HSD1. Compound 15 (IC 50 = 114 nM) with weak inhibitory activity against the key human cytochrome P450 enzymes and moderate stability in incubation with human liver microsomes is worthy of further development. Importantly, compound 41 (IC 50 = 280 nM) provides a new lead that incorporates an adamantyl group surrogate and should enable further series diversification.
UR - http://www.scopus.com/inward/record.url?scp=84867573474&partnerID=8YFLogxK
UR - http://dx.doi.org/10.1016/j.bmc.2012.08.056
U2 - 10.1016/j.bmc.2012.08.056
DO - 10.1016/j.bmc.2012.08.056
M3 - Article
AN - SCOPUS:84867573474
VL - 20
SP - 6394
EP - 6402
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
SN - 0968-0896
IS - 21
ER -