The development and SAR of pyrrolidine carboxamide 11β-HSD1 inhibitors

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

“…A study from Pfizer has described a fourth structure of the guinea pig protein, Protein Data Bank (PDB) code 3LZ6, for which, at the time of writing, the coordinates have not yet been released [52]. This structure has in it an inhibitor, 28 (Figure 4), an adamantyl amide derivative with K i = 1.4 nM against the human enzyme and K i = 0.63 nM against the mouse enzyme.…”

Crystal structure of N-(adamantan-1-yl)-4-phenylpiperazine-1-carbothioamide, C21H29N3S

“…In addition, numerous adamantane derivatives were reported to exhibit potent anticancer [9,10], bactericidal, fungicidal [11,12] and antimalarial [13] activities. Moreover, various N-(1-and 2-adamantyl)carboxamides and N-(substituted)carbothioamides were reported to display diverse pharmacological activities [14][15][16][17]. As a part of our ongoing research interest in the chemotherapeutic [18][19][20][21] and structural [22,23] properties of adamantane derivatives, we recently reported the synthesis, antibacterial and hypoglycemic activities of the title compound [21], and we report herein its crystal structure.…”

Chapter 5. 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Inhibitors in Development

“…79 Pfizer have subsequently reported a series of pyrrolidine carboxamide inhibitors developed from the adamantyl amide 41 ( Figure 5.9). 81 A lead compound PF-877423 (42) is potent against both human (K i 5 1.4 nM) and mouse (K i 5 0.63 nM) and retains good activity in a cell assay (IC 50 5 4.2 nM). The compound has moderate metabolism in human liver microsomes (Cl int 5 44 mL/min/kg) and showed dose dependent in vivo activity in a cortisone to cortisol mouse model with a maximal effect of 82% at 100 mg/kg and a calculated dose for 50% inhibition of 5 mg/kg.…”