Cortisol and the glucocorticoid receptor signaling pathway have been implicated in the development of diabetes and obesity. The reduction of cortisone to cortisol is catalyzed by 11beta-hydroxysteroid dehydrogenase type I (11beta-HSD1). 2,4-Disubsituted benzenesulfonamides were identified as potent inhibitors of both the human and mouse enzymes. The lead compounds displayed good pharmacokinetics and ex vivo inhibition of the target in mice. Cocrystal structures of compounds 1 and 20 bound to human 11beta-HSD1 were obtained. Compound 20 was found to achieve high concentrations in target tissues, resulting in 95% inhibition in the ex vivo assay when dosed with a food mix (0.5 mg of drug per g of food) after 4 days. Compound 20 was efficacious in a mouse diet-induced obesity model and significantly reduced fed glucose and fasted insulin levels. Our findings suggest that 11beta-HSD1 inhibition may be a valid target for the treatment of diabetes.

Cortisol and the glucocorticoid receptor (GR) signaling pathway has been linked to the development of diabetes and metabolic syndrome. In vivo, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes the conversion of inactive cortisone to its active form, cortisol. Existing clinical data have supported 11β-HSD1 as a valid therapeutic target for type 2 diabetes. In our research program, (R)-1,1,1-trifluoro-2-(3-((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-ylsulfonyl)phenyl)propan-2-ol (HSD-016) was discovered to be a potent, selective, and efficacious 11β-HSD1 inhibitor and advanced as a clinical candidate. Herein, a reliable and scalable synthesis of HSD-016 is described. Key transformations include an asymmetric synthesis of a chiral tertiary alcohol via Sharpless dihydroxylation, epoxide formation, and subsequent mild reduction. This route ensured multikilogram quantities of HSD-016 necessary for clinical studies.

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes the conversion of inactive glucocorticoid cortisone to its active form, cortisol. The glucocorticoid receptor (GR) signaling pathway has been linked to the pathophysiology of diabetes and metabolic syndrome. Herein, the structure−activity relationship of a series of piperazine sulfonamide-based 11β-HSD1 inhibitors is described. (R)-3,3,3-Trifluoro-2-(5-(((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-yl)sulfonyl)thiophen-2-yl)-2-hydroxypropanamide 18a (HSD-621) was identified as a potent and selective 11β-HSD1 inhibitor and was ultimately selected as a clinical development candidate. HSD-621 has an attractive overall pharmaceutical profile and demonstrates good oral bioavailability in mouse, rat, and dog. When orally dosed in C57/BL6 diet-induced obesity (DIO) mice, HSD-621 was efficacious and showed a significant reduction in both fed and fasting glucose and insulin levels. Furthermore, HSD-621 was well tolerated in drug safety assessment studies. KEYWORDS: 11β-hydroxysteroid dehydrogenase type I (HSD1), diet-induced obesity, type II diabetes, piperazine sufonamides G lucocorticoid hormones are key regulators of a wide range of biological processes such as the control of immune and stress responses as well as modulation of energy metabolism. Glucocorticoids (cortisol in humans and corticosterone in mice and rats) stimulate hepatic glucose production and suppress insulin-mediated glucose uptake in peripheral tissues (i.e., adipose and muscle). 11β-Hydroxysteroid dehydrogenase type I (11β-HSD1), 1−7 a reduced β-nicotinamide adenine dinucleotide phosphate (NADPH)-dependent enzyme, predominantly acts as a reductase in vivo, converting inactive, nonreceptor binding cortisone to active, receptor-binding cortisol in tissues such as liver, adipose, vasculature, brain, and macrophages. 8 The enzyme is a tetramer consisting of two dimers each with an independent active site. 8 It has been proposed that 11β-HSD1 reductase activity exists predominantly in metabolic tissues because of the increased ratio of NADPH to β-nicotinamide adenine dinucleotide phosphate (NADP) within the endoplasmic reticulum (ER) lumen and/or through direct interactions with NADPH-generating hexose-6-phosphate dehydrogenase (H6PDH), an enzyme that has been associated with cortisone reductase deficiency in humans. 9 Cortisone itself is generated by the action of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) with cortisol using NADP as a cofactor. 11β-HSD1 levels are highest in liver and adipose tissues as well as in the central nervous system, whereas 11β-HSD2 is mainly expressed in the kidney and colon. 10 The rationale for 11β-HSD1 as a therapeutic target for the treatment of diabetes and the metabolic syndrome is based on data from tissue-specific overexpression in transgenic mice 11,12 and mice 11β-HSD knockout experiments. 13,14 In addition, 11β-HSD1 activity in adipose tissue also correlates positively with body mass index (BMI), fat percentage, and fas...