Discovery of Adamantyl Heterocyclic Ketones as Potent 11β‐Hydroxysteroid Dehydrogenase Type 1 Inhibitors

Abstract

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) plays a key role in converting intracellular cortisone to physiologically active cortisol, which is implicated in the development of several phenotypes of metabolic syndrome. Inhibition of 11β-HSD1 activity with selective inhibitors has beneficial effects on various conditions, including diabetes, dyslipidemia and obesity, and therefore constitutes a promising strategy to discover novel therapies for metabolic and cardiovascular diseases. A series of novel adamantyl heterocyclic ketones provides potent and selective inhibitors of human 11β-HSD1. Lead compounds display low nanomolar inhibition against human and mouse 11β-HSD1 and are selective with no activity against 11β-HSD2 and 17β-HSD1. Selected potent 11β-HSD1 inhibitors show moderate metabolic stability upon incubation with human liver microsomes and weak inhibition of human CYP450 enzymes.

Synthesis and evaluation of thiadiazole derivatives as inhibitors of 11β-hydroxysteroid dehydrogenase type 1

“…20 We therefore pursued the synthesis of compounds 19-30, which have the phenyl ethanone moiety tethered to the thiadiazole through either a sulphoxide or sulphone linker ( Table 2). The bicyclic analogues 19 and 20 both show reduced activity when measured at 1 mM, as does the para-methoxy compound 21 with a sulphoxide linker.…”

“…[19][20][21] We previously reported that compounds 1 and 2 ( Fig. 1) are highly active 11b-HSD1 inhibitors when tested on an HEK293 cell line transfected with the human 11b-HSD1 gene.…”

Adamantyl Ethanone Pyridyl Derivatives: Potent and Selective Inhibitors of Human 11β‐Hydroxysteroid Dehydrogenase Type 1

“…The inhibitory activities of compounds 1-4 were measured in HEK293 cells transfected with the human HSD11B1 gene. [38,[41][42] Scheme 1. Synthesis of the adamantyl ethanone compounds (for Ar, see Tables 1-3).…”

“…[39,40] We previously identified some adamantyl ethanone derivatives as potent inhibitors of human 11b-HSD1. [41,42] Compounds 2-4 exhibit high inhibitory activity with nanomolar IC 50 values when examined in a HEK293 cell line stably transfected with the HSD11B1 gene ( Figure 1). These compounds also show reasonable metabolic stability when incubated with human liver microsomes.…”

“…The inhibitory activities of compounds 1–4 were measured in HEK293 cells transfected with the human HSD11B1 gene. [ 38 , 41 – 42 ]…”