Design and Synthesis of (R)‐1‐Arylsulfonylpiperidine‐2‐carboxamides as 11β‐Hydroxysteroid Dehydrogenase Type 1 Inhibitors

Abstract

R adamantly beats S: 11β-HSD1 is a target for treating metabolic syndrome. The R isomer 5 was selected as a starting point for optimization and SAR studies. Inhibitor 8 w emerged after several rounds of optimization, showing cross-species inhibition of human and mouse 11β-HSD1. It also displays a good DMPK profile in vitro, and was advanced to PK/PD evaluations in vivo. The results confirmed its dose-dependent activity in mice.

Medicinal Chemistry of Inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1)

“…Pharmacokinetics in mouse showed high clearance (130 mL min −1 kg −1 ) and low oral bioavailability (3%); however, ex vivo activity was demonstrated in mice after intraperitoneal dosing. 108 1,2,4-Oxadiazoles were successfully used as bioisosteric replacements of the amide group with further optimization of the sulfonamide to amide linker leading to 94. 109 Potency against human 11β-HSD1 was retained (IC 50 = 3.3 nM); however, mouse potency was significantly reduced (<30% activity at 1 μM).…”

“…Alternative piperidineamide scaffolds were also found to be active, with hydroxyladamantyl­amide 93 being potent against human (IC 50 = 1.2 nM) and mouse (IC 50 = 15 nM) 11β-HSD1. Pharmacokinetics in mouse showed high clearance (130 mL min –1 kg –1 ) and low oral bioavailability (3%); however, ex vivo activity was demonstrated in mice after intraperitoneal dosing . 1,2,4-Oxadiazoles were successfully used as bioisosteric replacements of the amide group with further optimization of the sulfonamide to amide linker leading to 94 .…”

Identification of 11β-HSD1 inhibitors through enhanced sampling methods

“…Several small-molecule 11b-HSD1 inhibitors were developed in the preceding years, but only a few have progressed into phase III clinical trials. 8,9 Although certain new molecules have substantial anti-diabetic activities, their mechanism of action remains unknown due to obscure target pathways. Therefore, the requirement has been sustained over the years to develop effective and more competent inhibitors of 11b-HSD1.…”

Molecular Modeling Studies of 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors through Receptor-Based 3D-QSAR and Molecular Dynamics Simulations

“…A number of small molecular inhibitors of 11β-HSD1 have been disclosed in the past few years [17,18,19], and a few of compounds have got into clinical trials studies. Incyte’s small molecule inhibitor INCB-13739 had completed phase I trials and was progressed into phase II trials in 2007.…”