2-Amino-1,3-thiazol-4(5H)-ones as Potent and Selective 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors: Enzyme−Ligand Co-Crystal Structure and Demonstration of Pharmacodynamic Effects in C57Bl/6 Mice

Abstract

11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) has attracted considerable attention during the past few years as a potential target for the treatment of diseases associated with metabolic syndrome. In our ongoing work on 11beta-HSD1 inhibitors, a series of new 2-amino-1,3-thiazol-4(5 H)-ones were explored. By inserting various cycloalkylamines at the 2-position and alkyl groups or spirocycloalkyl groups at the 5-position of the thiazolone, several potent 11beta-HSD1 inhibitors were identified. An X-ray cocrystal structure of human 11beta-HSD1 with compound 6d (Ki=28 nM) revealed a large lipophilic pocket accessible by substitution off the 2-position of the thiazolone. To increase potency, analogues were prepared with larger lipophilic groups at this position. One of these compounds, the 3-noradamantyl analogue 8b, was a potent inhibitor of human 11beta-HSD1 (Ki=3 nM) and also inhibited 11beta-HSD1 activity in lean C57Bl/6 mice when evaluated in an ex vivo adipose and liver cortisone to cortisol conversion assay.

Crystal Structures of 11β-Hydroxysteroid Dehydrogenase Type 1 and Their Use in Drug Discovery

“…The fluorophenyl ring in both 3BZU and 3EY4 makes contacts with T124, S125, L126, V180, A223, A226 and V227 and has an edge on interaction with the ring of Y183 at a distance of approximately 4 Å. The thiazol-4-one 5-position substituents in 3BZU contact L171, Y177, G216, L217 and M233 and the equivalent contacts in the 3EY4 structure are to the same residues plus A172, V180 and V231 [38][39][40]45]. …”

“…Details of eighteen crystal structures of human 11β-HSD1 (Table 1) have been released [35][36][37][38][39][40][41][42][43][44][45][46][47][48]; these have a variety of inhibitors bound (9-26; Figure 3). In rodents, 11β-HSD1 catalyzes the reduction of 11-dehydrocorticosterone (1b) to corticosterone (2b; Figure 1).…”

Discovery of Adamantyl Ethanone Derivatives as Potent 11β‐Hydroxysteroid Dehydrogenase Type 1 (11β‐HSD1) Inhibitors

“…Fourteen of the publicly available crystal structures of human 11b-HSD1 (1XU7, [49] 1XU9, [49] 2BEL, 2ILT, [43] 2IRW, [50] 2RBE, [51] 3BYZ, [52] 3BZU, [53] 3CH6, [54] 3CZR, [55] 3D3E, [56] 3D4N, [56] 3D5Q, [57] 3EY4 [44] and 3FRJ [58] ) were superimposed to determine the shape, volume and flexibility of the substrate binding site. The NADP(H) molecules from all fourteen structures were found to be superimposable-the different inhibitors have little influence on the structure of the protein around the NADP(H).…”

11β-Hydroxysteroid Dehydrogenase Type 1 and the Metabolic Syndrome

“…Several and distinct selective 11 -HSD1 inhibitors are being produced, developed and tested in vitro, ex vivo and in vivo, in normal animals, rodent models of metabolic alterations or disease (hyperglycemia, dyslipidemia, atherosclerosis, IR, T2DM, obesity, diet-induced obesity and/or MetSyn) and some of them already in humans, healthy or not (Alberts et al, 2002;Alberts et al, 2003;Barf et al, 2002;Bhat et al, 2008;Bujalska et al, 2008a;Cho et al, 2009;Cooper & Stewart, 2009;Coppola et al, 2005;Courtney et al, 2008;Feig et al, 2011;Gathercole & Stewart, 2010;Ge et al, 2010;Hermanowski-Vosatka et al, 2005;Hollis & Huber, 2011;Hughes et al, 2008;Hult et al, 2006;Johansson et al, 2008;Julian et al, 2008;J. Liu et al, 2011;Morgan et al, 2009;Morgan & Tomlinson, 2010;Morton, 2010;Park et al, 2011;Rosenstock et al, 2010;U.…”

“…The 24 h ambulatory blood pressure measurements data (from the subset of patients who participated in ambulatory blood pressure measurements) suggest that MK-0736 has blood pressurelowering efficacy over a 24 h period not adequately represented by measuring sitting diastolic blood pressure and sitting systolic blood pressure, notably a greater blood pressure-lowering effect during daytime than during night-time (S. Shah et al, 2011). 11 -HSD1 inhibitors may improve a number of metabolic disturbances, unlike current available anti-diabetic compounds, that occur in obesity, T2DM and/or MetSyn patients, as seen from genetically engineered animal studies (Kotelevtsev et al, 1997;Morton et al, 2001;Morton et al, 2004) as well as from animal (Alberts et al, 2002;Alberts et al, 2003;Barf et al, 2002;Cooper & Stewart, 2009;Feng et al, 2010;Gathercole & Stewart, 2010;Hermanowski-Vosatka et al, 2005;Johansson et al, 2008;J. Liu et al, 2011;Livingstone & Walker, 2003;Morgan et al, 2009;Park et al, 2011;Taylor et al, 2008;Véniant et al, 2010;S.…”