2-(S)-Phenethylaminothiazolones as Potent, Orally Efficacious Inhibitors of 11β-Hydroxysteriod Dehydrogenase Type 1

Abstract

11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) is the enzyme that converts cortisone to cortisol. A growing body of evidence suggests that selective inhibition of 11beta-HSD1 could potentially treat metabolic syndrome as well as type 2 diabetes. Through modification of our initial lead 1, we have discovered trifluoromethyl thiazolone 17. This compound had a Ki of 22 nM, possessed low in vivo clearance, and showed a 91% inhibition of adipose 11beta-HSD1 enzymatic activity in a mouse ex vivo pharmacodynamic model.

Structural Characterization and Pharmacodynamic Effects of an Orally Active 11β‐Hydroxysteroid Dehydrogenase Type 1 Inhibitor

“…Through medicinal chemistry efforts (19), we identified a potent and selective inhibitor of human 11β‐HSD1 (Figure 1). This compound is from a thiazolone series that we reported recently (19), a chemical class that is completely different from previously reported 11β‐HSD1 inhibitors (14). In a biochemical assay, compound 2922 exhibited an IC 50 value of 14 ± 5 n m for human 11β‐HSD1 (Figure 2A).…”

“… Chemical structure of compound 2922. Compound 2922 [(S)‐2‐((S)‐1‐(2‐fluorophenyl)ethylamino)‐5‐methyl‐5‐(trifluoromethyl)thiazol‐4(5H)‐one] is a novel small molecule inhibitor of 11β‐HSD1 from a thiazolone series (19). …”

“…Corticosterone and adrenocorticotropic hormone (ACTH) RIA kits were obtained from MP Biomedicals (Solon, OH, USA). Compound 2922 was synthesized as described previously (19). Lot #4 of compound 2922 was used in the biochemical and cell‐based assays of this report ( n = 5).…”

Inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1 in Antidiabetic Therapy

“…The first three compounds in Table 1 exhibit higher potency for rat 11b-HSD1 than the human enzyme (Richards et al 2006). The other three compounds, however, have higher potency for human 11b-HSD1 than the mouse enzyme (Rohde et al 2007;Sorensen et al 2006;St Jean et al 2007). Not all 11b-HSD1 inhibitors have species selectivity with respect to human and rodent activities; there are many compounds with comparable human and rodent potency values.…”

“…Several well studied 11b-HSD1 inhibitors include compound 544 from Merck (Hermanowski-Vosatka et al 2005), compound 2922 from Amgen (Hale et al 2008;St Jean et al 2007), and compound PF-915275 from Pfizer (Bhat et al 2008). The selectivity of both compounds 544 and 2922 over other human targets were demonstrated by counter screens or assays (Hale et al 2008;HermanowskiVosatka et al 2005).…”