Discovery and Biological Evaluation of Potent and Orally Active Human 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors for the Treatment of Type 2 Diabetes Mellitus

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.

Multi-Targeted Molecular Docking, Pharmacokinetics, and Drug-Likeness Evaluation of Okra-Derived Ligand Abscisic Acid Targeting Signaling Proteins Involved in the Development of Diabetes

“…Cortisol promotes pre-adipocyte differentiation into mature adipocytes, resulting in adipose tissue hyperplasia. By modulating cortisone/cortisol levels, selective inhibition of this enzyme can be a novel treatment for T2DM and hyperlipidemia [ 16 , 17 , 18 , 19 ]. Obesity, diabetes, wound healing, and muscular atrophy are glucocorticoid-related disorders, and inhibiting 11β-HSD1 has many therapeutic values, including T2DM and hyperlipidemia.…”

<i>In Silico</i> Characterization of a Novel Bioactive Compound derived from <i>Psidium guajava</i> 4-[5-(Pyridin-4-yl)-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-amine: A Potential Inhibitor for Targeting Signaling Proteins involved in Diabetes Development

“…Inhibiting this enzyme may offer a good treatment for type 2 diabetes by adjusting cortisone/cortisol levels. [46][47][48][49] An analysis by PLIP [50] online server for active site amino acids of chain A of 11 β-HSD1 enzyme (4K1L) with crystal structure of NDP (NADP) molecule exhibits hydrogen bonding with GLY41, SER43, LYS44, ILE46, ARG66, SER67, THR92, MET93, GLU94, ASN119, ILE121, TYR147, LYS187, ILE218, THR220, THR222 including other water and salt bridges.…”

11β-Hydroxysteroid Dehydrogenase Type 1 as a Potential Treatment Target in Cardiovascular Diseases

“…The biological activity of a compound depends on its chemical structure, hence structural fragments characteristic for inhibitors that have reached the stage of clinical trials are observed in the new tested compounds. In vitro studies were carried out for various structures, of which the group of compounds containing a thiazole ring [ 117 , 133 , 134 , 135 ] or its partially hydrogenated form, thiazol-4-one [ 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 ], seems to be the most numerous and promising ( Figure 5 ). Compounds containing fused systems with a thiazole ring [ 144 , 145 ] and other various heterocyclic systems with nitrogen atoms [ 146 , 147 , 148 , 149 , 150 , 151 , 152 ] were also analyzed as potential selective inhibitors of 11β-HSD1 ( Figure 6 ).…”

“… Selected selective 11β-HSD1 inhibitors with different heterocyclic moiety in in vitro studies. Data refer to tests for human (h) or murine (m) 11β-HSD1 [ 135 , 145 , 147 , 152 , 154 , 155 , 156 , 157 , 158 , 159 , 160 ]. …”