Abstract
We synthesized and evaluated novel 5-[2-(thiophen-2-yl)propan-2-yl]-4H-1,2,4-triazole derivatives as 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors. Optimization of the thiophene ring and the substituents on the 1,2,4-triazole ring produced 3,4-dicyclopropyl-5-{2-[3-fluoro-5-(trifluoromethyl)thiophen-2-yl]propan-2-yl}-4H-1,2,4-triazole monohydrochloride (9a), which showed potent and selective inhibitory activity against human 11β-HSD1. Compound 9a was also metabolically stable against human and mouse liver microsomes. Oral administration of 9a to diabetic ob/ob mice lowered corticosterone levels in adipose tissue, and thereby reduced plasma glucose and insulin levels in a dose-dependent manner.
References
Jan 1, 1984·Journal of Inherited Metabolic Disease·H MorishitaY Suzuki
Aug 1, 1995·Nature Genetics·T MuneP C White
Jun 1, 1994·Diabetes·S I TaylorY Imai
Dec 1, 1995·Journal of Computer-aided Molecular Design·G JonesR C Glen
Apr 4, 1997·Journal of Molecular Biology·G JonesR Taylor
Jun 24, 2000·Diabetes·C T Montague, S O'Rahilly
Mar 10, 2001·The Journal of Clinical Endocrinology and Metabolism·E RaskB R Walker
Apr 11, 2001·The Journal of Biological Chemistry·E A WalkerP M Stewart
Jun 6, 2003·The Journal of Clinical Endocrinology and Metabolism·Robert S LindsayBrian R Walker
Jul 4, 2003·The Journal of Clinical Investigation·Hiroaki MasuzakiJeffrey S Flier
Mar 11, 2004·Chemical Reviews·Stuart A RossMinghan Wang
Apr 20, 2004·Cellular and Molecular Life Sciences : CMLS·M HultU Oppermann
Sep 16, 2008·Bioorganic & Medicinal Chemistry·Hua TuZhulun Wang
May 29, 2009·Bioorganic & Medicinal Chemistry Letters·Michael SiuJennifer E Vogel
May 15, 2010·Journal of Medicinal Chemistry·Murielle M VéniantMinghan Wang
Jan 29, 2011·Diabetes, Obesity & Metabolism·P U FeigK D Kaufman
Jul 9, 2011·The Journal of Organic Chemistry·Zhao-Kui WanEddine Saiah
Jan 4, 2012·Diabetes Care·UNKNOWN American Diabetes Association
Jul 13, 2013·Bioorganic & Medicinal Chemistry Letters·Thomas BöhmeKurt Ritter
Jan 16, 2014·Journal of Medicinal Chemistry·Frederick W GoldbergMartin J Wild
May 22, 2017·Bioorganic & Medicinal Chemistry·Linghang ZhuangDavid A Claremon