Discovery of 2-Alkyl-1-arylsulfonylprolinamides as 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors

Abstract

On the basis of scaffold hopping, a novel series of 2-alkyl-1-arylsulfonylprolinamides was discovered as 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) inhibitors. A representative compound 4ek, obtained through SAR and structure optimization studies, demonstrates excellent in vitro potency against 11β-HSD-1 and dose-dependent in vivo inhibition of 11β-HSD-1 in a prednisone/prednisolone transformation biomarker study in mice.KEYWORDS: metabolic syndrome, enzyme inhibitor, 11β-hydroxysteroid dehydrogenase type 1, sulfonamide, 2-alkylproline, prolinamide G lucocorticoid receptor (GR) signaling plays a significant role in metabolic regulation, and defects in this signaling pathway have been implicated in the development of several phenotypes of metabolic syndrome.1 GR signaling depends not only on the circulating cortisol levels but also on the intracellular production of cortisol through reduction of cortisone, the inactive glucocorticoid. The enzymes catalyzing the conversion between cortisone and cortisol are 11β-hydroxysteroid dehydrogenases (11β-HSDs). Among them, the type 1 isoform (11β-HSD-1), highly expressed in liver and adipose tissue, predominantly reduces cortisone to cortisol, and the type 2 isoform (11β-HSD-2), primarily expressed in kidney, oxidizes cortisol to cortisone. A potential role for 11β-HSD-1 inhibitors in metabolic syndrome, type 2 diabetes, and obesity has been established using transgenic mice.2−4 On the basis of these findings, in recent years, 11β-HSD-1 is recognized as a promising target in metabolic disease. 1−4In the past decade, industrial and academic researchers have reported several classes of 11β-HSD-1 inhibitors with varied scaffolds, including sulfonamides (e.g., BVT-14225, 1a), amides (e.g., PF-877423, 2) (Figure 1), triazoles (e.g., Merck 544), and thiazolones (e.g., AMG-221).5−8 In a phase II clinical trial, 11β-HSD-1 inhibitor INCB-13739 (structure undisclosed) significantly improved insulin sensitivity in type 2 diabetes patients who failed on metformin treatment and lowered triglyceride and cholesterol levels of patients with hyperlipidaemia and hypertriglyceridemia.9 Currently, other examples such as PF-915275, MK-0916, and AZD-4071 are being evaluated in phase I/II trials for potential oral treatment of metabolic diseases. 10−12We recently disclosed a new series of sulfonamides (e.g., 1b, Figure 1) with high inhibitory activity against 11β-HSD-1, and compound 1b showed a short duration of action in a pharmacodynamics (PD) model. 13 As part of our continuing

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

“…Mouse pharmacokinetics remained problematic with high clearance (60 mL min –1 kg –1 ) and low bioavailability (3%). A dose dependent reduction in mouse in vivo inhibition of 11β-HSD1 was demonstrated by dosing of 95 (3–30 mg/kg) by intraperitoneal dosing …”

Discovery of Clinical Candidate 2-((2S,6S)-2-Phenyl-6-hydroxyadamantan-2-yl)-1-(3′-hydroxyazetidin-1-yl)ethanone [BMS-816336], an Orally Active Novel Selective 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor

“…These and other preclinical findings build a strong case that inhibition of 11β-HSD1 may be an efficacious approach for the treatment of metabolic syndrome. As a result, much attention has been focused on the discovery and development of inhibitors of this enzyme. − In clinical trials, Incyte, Merck, and others have demonstrated that 11β-HSD1 inhibitors improved glycaemic control, lipid profiles, and blood pressure with modest weight loss . In addition to this indication, we recently explored and proposed atheroprotection as an emerging indication for this target.…”

Synthesis of (R)-Boc-2-methylproline via a Memory of Chirality Cyclization. Application to the Synthesis of Veliparib, a Poly(ADP-ribose) Polymerase Inhibitor

“…(R)-1-(tert-Butoxycarbonyl)-2-methylpyrrolidine-2-carboxylic Acid (3a). 19 A pressure reactor was charged with 5% Pd/C (2.56 g of 5% Pd/C, 3 wt %) and purged with nitrogen. The (R)-Boc-2methylproline benzyl ester (10a, 146.32 g of 59.4 wt %, 87.13 g = 272.79 mmol) was added, along with 426 mL of denatured EtOH.…”