Medicinal Chemistry of Inhibitors of 11Î²-Hydroxysteroid

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Medicinal Chemistry of Inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) James S. Scott,* Frederick W. Goldberg, and Andrew V. Turnbull AstraZeneca Innovative Medicines, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, U.K.

ABSTRACT: 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is the enzyme primarily responsible for the regulation of intracellular cortisol levels. Inhibition of 11β-HSD1 is an attractive mechanism for the treatment of obesity and other elements of the metabolic syndrome. Emerging literature also supports a potential role in the treatment of other unmet medical needs including Alzheimer’s disease, vascular inflammation, cardiovascular disease, and glaucoma. The aim of this article is to review the medicinal chemistry literature around small molecule approaches to developing synthetic inhibitors of 11β-HSD1 and to highlight key compounds that have resulted from the efforts of both industrial and academic groups. The reported data from 11βHSD1 inhibitors that have progressed into the clinic are summarized followed by a perspective from the authors.

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GLUCOCORTICOIDS AND THE METABOLIC SYNDROME The metabolic syndrome is a collection of abnormalities including resistance to insulin, obesity, dyslipidemia, hyperglycemia, and hypertension that represents a major risk factor for type 2 diabetes and cardiovascular disease.1 The pathogenesis of the metabolic syndrome is complex and influenced by a number of mechanisms. Among these, glucocorticoid synthesis and metabolism have been proposed to play a key role.2,3 Glucocorticoids (GCs) are synthesized in and released from the adrenal cortex with a strong circadian rhythm. Secretion of GCs is under the control of the hypothalamic−pituitary− adrenal (HPA) axis. Activation of the HPA axis by stress stimulates the secretion of corticotrophin-releasing factor (CRF) into the hypophyseal portal circulation, resulting in the release of adrenocorticotropin (ACTH) from the anterior pituitary gland. ACTH in turn stimulates the secretion of GCs from the adrenal. In the acute setting, as occurs in stress, GCs actually have a catabolic action making substrates available for mitochondrial oxidation. However, excess of GC, as seen in Cushing’s syndrome, leads to increased fat accumulation, preferentially in the visceral depot, hepatic triacylglycerol (TAG) accumulation, insulin resistance, and hyperglycaemia. It also leads to increased cardiovascular risk via hypertension and dyslipidemia. These physiological and pathophysiological effects of GCs occur because of the action of GCs on a number © XXXX American Chemical Society

of tissues, including adipose tissue, liver, muscle, the blood vessel wall, pancreas, and the central nervous system.

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11β-HYDROXYSTEROID DEHYDROGENASE TYPE 1 (11β-HSD1) 11β-Hydroxysteroid dehydrogenases (11β-HSD) are prereceptor enzymes that regulate the intracellular availability of active GC to bind and activate the glucocorticoid receptor (GR). The biology and translational aspects of 11β-HSD1 have been comprehensively reviewed.4 Briefly, 11β-HSD1 and 11β-HSD2 are products of two different genes and have different tissue distributions and physiological roles. 11β-HSD2 was the first isoform to be identified and is an NAD+ dependent dehydrogenase. It converts the active GC, cortisol (in man, corticosterone in mouse/rat), to the inactive, cortisone (in man, DHC in rodents) (see Figure 1). It is expressed predominantly in mineralocorticoid target tissues such as the kidney and colon, and its function is to protect the mineralcorticoid receptor from activation by cortisol. On the other hand, 11β-HSD1 is widely distributed and importantly is expressed in key metabolic tissues such as liver, adipose tissue, and muscle. 11β-HSD1 is bidirectional, able to act as both an oxoreductase (activating GC) and a dehydrogenase (inactivating GC). However, in intact cells such as hepatocytes and Received: September 23, 2013

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dx.doi.org/10.1021/jm4014746 | J. Med. Chem. XXXX, XXX, XXX−XXX

Journal of Medicinal Chemistry

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HSD1 in adipose tissue.12 This model recapitulated virtually all aspects of the human metabolic syndrome, importantly without raising circulating glucocorticoid levels. These animals’ phenotype of abdominal obesity, hyperglycemia, dyslipidaemia, and hypertension was driven by elevated levels of corticosteroid in adipose tissue and the portal circulation. This empirical set of observations led to a drive to focus attention on the discovery and development of 11β-HSD1 inhibitors that were effective at inhibiting the enzyme in adipose tissue as well as liver.

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PRECLINICAL EVIDENCE FOR 11β-HSD1 IN TREATMENT OF ALTERNATIVE DISEASE INDICATIONS Elevated cortisol is also associated with cognitive dysfunction and neurotoxicity, and glucocorticoids increase amyloid Aβ in models of Alzheimer’s disease. 11β-HSD1 is highly expressed in brain regions important for cognition and is increased in animal models of Alzheimer’s disease. Transgenic overexpression of 11β-HSD1 in brain exacerbates age-associated cognitive dysfunction, while 11β-HSD1 knockout mice are protected.13,14 More recently, inhibition of 11β-HSD1 has been proposed as a strategy to reduce vascular inflammation15 and as having potential utility in the treatment of cardiovascular disease.16

Figure 1. Interconversion by 11β-HSD1 and 11β-HSD2 of cortisone and cortisol in humans and 11-dihydrocorticosterone (11-DHC) and corticosterone in rodents.

adipocytes 11β-HSD1 activity is predominantly oxoreductive, supported by a higher affinity for cortisone than cortisol. Circulating cortisol levels are not increased in human obesity and metabolic syndrome; however, there is evidence of altered glucocorticoid metabolism.5 For example, increased tissue 11βHSD1 expression and activity have been demonstrated, notably in metabolic tissues including liver and adipose in these conditions.6−8 This has led to the widely held belief that elevated 11β-HSD1 in tissues may be contributing to metabolic disease.9,10

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CARBENOXOLONE Carbenoxolone (CBX) (3) is the hemisuccinate ester derivative of glycyrrhetinic acid, a natural product found in liquorice root (Figure 2).17 It has moderate potency in terms of inhibition of 11β-HSD1 but is unselective against 11β-HSD2 which has limited its use as a clinical compound.18 Dosing of compound 3 to healthy human males resulted in improvements in insulin sensitivity.19 Subsequent dosing of 3 to lean type 2 diabetics resulted in improved hepatic insulin sensitivity and reduced glucose production and glycogenolysis. However, no effects on gluconeogenesis, peripheral glucose uptake, or insulin-mediated suppression of plasma free fatty acids were observed.20 Unfortunately, attempted treatment of obese patients with compound 3 did not result in beneficial effects in terms of insulin sensitivity.21 The lack of efficacy observed in obese as

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PRECLINICAL EVIDENCE FOR 11β-HSD1 IN TREATMENT OF THE METABOLIC SYNDROME A number of mouse genetic models, in which 11β-HSD1 (or 11β-HSD2) have been either overexpressed or deleted, have been generated. The phenotypes of these models have been broadly consistent with 11β-HSD1 playing a role in the development of obesity and insulin resistance as well as other (e.g., atherosclerosis) cardiovascular pathologies in mice. For example, resistance to weight gain and visceral fat accumulation and improvements in glucose tolerance and lipid profiles have been described in global 11β-HSD1 global knockout mice.11 Of major significance to the field of 11β-HSD1 drug discovery was the description of the mouse model that overexpressed 11β-

Figure 2. Structure of the 11β-HSD1 and 11β-HSD2 inhibitor carbenoxolone together with the ligand binding pocket (PDB code 2BEL) and an interaction map showing the directional interactions. B



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of 4 to KKAy mice dosed at 167 mg kg−1 day−1 using osmotic minipumps lowered mRNA levels encoding for phosphoenolpyruvate carboxykinase and glucose 6-phosphatase, two enzymes important in hepatic glucose production. These data were supportive of the role of 11β-HSD1 in gluconeogenesis and indicated the potential for small molecule inhibitors of 11βHSD1 that are selective over 11β-HSD2 to impact glucose homeostasis, at least in preclinical models. Conversely, compound 5 is more active against the human (IC50 = 52 nM) than the mouse (IC50 = 284 nM) isoform. Biovitrum, in collaboration with Amgen, took a structurally related compound 6 (BVT-3498) into clinical trials. The structure of 6 is detailed in a patent application, although no biological data were included.31 This compound successfully completed phase I trials and advanced into phase II trials in 2002, but development was stopped in 2005 for undisclosed reasons. Work has also been reported on a series of piperidine amides identified from high throughput screening (HTS) with compound 7 having weak enzyme potency (Ki = 110 nM).32 A series of oxazolones such as 8, related to the thiazolones codeveloped with Amgen, have also been described with the example shown having reasonable potency in enzyme (Ki = 19 nM) and adipocyte (IC50 = 95 nM) assays and low intrinsic clearance in human and rat microsomes.33 Researchers at Amgen have described the optimization of a hit 9, identified by high throughput screening, into a lead compound 10 (Figure 4).34 The aniline ring of related compounds such as 11 was replaced with a benzyl group leading to the identification of a tool compound 12 (compound 2922, BVT-116429).35 This was equipotent in both enzyme and cell assays (IC50 = 14 nM) against the human isoform but less potent in mouse (IC50 = 161 nM). The compound was selective over 11β-HSD2, 17β-HSD1, and glucocorticoid receptor in addition to 60 other human targets (90% inhibition at 2 h post dose at 10 mg/kg. Dose-dependent (1−10 mg/kg) suppression of prednisone to prednisolone conversion (mediated by 11βHSD1 activity in the liver) was also demonstrated in mice with a maximal 70% reduction in the prednisolone/prednisone ratio at the top dose. At all doses where efficacy was observed, no changes in plasma corticosterone or ACTH levels were observed suggesting no up-regulation of the HPA axis was occurring. Efficacy in KKAy mice was demonstrated with compound 12 increasing adiponectin levels at doses of 3−30 mg/kg for 10 days. Fasting blood glucose levels were also decreased with a similar level of efficacy as rosiglitazone dosed at 5 mg/kg.37 Unfortunately, compound 12 was found to cause activation of the human pregnane X receptor (PXR). This can lead to upregulation of genes involved in drug metabolism, specifically cytochrome P450 (CYP) 3A4, which can in turn lead to increased metabolic clearance of drug and reduced efficacy. Compound 12 at 20 μM showed 45% of the effect of the positive control rifampicin at 12.5 μM. The PXR liability was successfully reduced through incorporation of polar functionality to give compounds such as 13. This retained good activity in both human enzyme (Ki = 35 nM) and cell (IC50 = 34 nM) and showed reduced PXR activation (10% relative to control at 20 μM). Dose dependent in vivo efficacy was demonstrated in a cynomolgus monkey model at doses of 0.3−30 mg/kg.38

opposed to lean patients has been ascribed to either a lack of adequate adipose tissue penetration with compound 3 or the fact that down-regulation of 11β-HSD1 function in the liver occurs in obese individuals. Inhibition of 11β-HSD2 can result in hypertension through activation of the mineralcorticoid receptor in the kidneys. This is a particular risk for patients with type II diabetes and other elements of the metabolic syndrome.22 The deficiencies of compound 3 in terms of the 11β-HSD2 activity assisted in driving early efforts in this field to develop highly selective inhibitors of 11β-HSD1. Compound 3 has also been used to demonstrate proof of concept in humans for improvements in cognitive function inhibition through 11βHSD1 inhibition.23 The structure of 3 in complex with human 11β-HSD1 has been determined, and interactions are highlighted in Figure 2. A key interaction is between the ketone of the substrate and Ser170, with this being mimicked in a number of disclosed inhibitor structures. The use of crystal structures in the discovery of 11β-HSD1 inhibitors has recently been reviewed and will therefore not be discussed in depth in this article.24,25

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MEDICINAL CHEMISTRY OF INHIBITORS OF 11β-HSD1 The aim of this article is to review the medicinal chemistry of small molecule approaches to developing synthetic inhibitors of 11β-HSD1 and to highlight key compounds that have resulted from the efforts of both industrial and academic groups.26 This article only refers to work published in academic journals and not the chemical equity described in patents filed on inhibitors of 11β-HSD1. This research has been comprehensively reviewed elsewhere.27−29 The review is structured into the work reported by each institution followed by a summary of the currently reported clinical data and concludes with a personal perspective on the current state of the field. Researchers at Biovitrum disclosed the first 11β-HSD1 inhibitors, 4 (BVT-2733) and 5 (BVT-14225), that were selective over human 11β-HSD2 (both IC50 > 10 μM) (Figure 3).30 Compound 4 had reasonable mouse potency (IC50 = 96

Figure 3. 11β-HSD1 inhibitors reported by Biovitrum.

nM) but was only weakly active against the human isoform (IC50 = 3341 nM). This combined with moderate mouse pharmacokinetics (F = 21%) made it a suitable in vivo tool with which to explore the potential of 11β-HSD1 as a mechanism for the treatment of type II diabetes. In KKAy mice, oral dosing twice daily (25, 50, 100 mg/kg) of compound 4 lowered blood glucose levels in a dose-dependent manner. A 1 week treatment C



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Figure 4. 11β-HSD1 thiazolone inhibitors reported by Amgen.

Figure 5. 11β-HSD1 sulfonamide, sulfone, and amide inhibitors reported by Amgen.

a dose dependent reduction in body weight was observed after 2 weeks. Compound 17 was progressed into phase I clinical trials, but development was terminated in April 2011.42 Subsequent reports have identified formation of a predominant metabolite 18 formed in humans that retained activity against human 11βHSD1 enzyme (Ki = 16 nM) and cell (IC50 = 13 nM) that potentially could contribute to the pharmacodynamic effects observed.43,44 A structurally distinct piperazinesulfonamide hit 19 was optimized with respect to potency leading to compound 20 (Figure 5).45 Further work, aimed at improving the aqueous solubility and rat pharmacokinetics, led to the identification of (R)-trifluoromethyl carbinol as a key replacement for a tertbutyl group in terms of improving metabolic stability and maintaining enzyme and cell potency as exemplified by compound 21.46,47 Compound 21 displayed high potency in an enzyme assay (IC50 = 0.7 nM) and retained potency in a cell assay (IC50 = 14 nM). It showed no inhibition of 11β-HSD2, hERG, or CYP3A4 (all >100 μM) and was orally bioavailable in rat (F = 41%). The compound was potent against the cynomolgus monkey enzyme (IC50 = 6 nM) and demonstrated efficacy in an acute ex vivo cynomolgus monkey model involving the conversion of [3H]cortisone in mesenteric fat samples collected 2 h postdose with an ED50 of 0.4 mg/kg.

Replacement of the aniline in compounds such as 14 with bridged cycloalkyl groups such as in 15 has also been reported.39 Subsequent work led to the identification of norbornyl as a favored substituent, and compounds such as 16 were optimized with respect to epimerization at the position α to the carbonyl leading to the identification of 17 (AMG-221, BVT-83370).40,41 The compound was potent against human enzyme (Ki = 13 nM) and cell (IC50 = 10 nM) assays. Selectivity was high against 11β-HSD2, 17β-HSD1, and glucocorticoid receptor (all IC50 > 10 μM) and a panel of 61 other human targets ( 15 μM) or transport by P-glycoprotein was observed. Oral bioavailability was good in mouse (F = 54%), rat (F = 34%), and dog (F = 50%) but low in monkey (F = 7%) because of high first pass metabolism, consistent with low liver microsomal stability in this species. In vivo inhibition of 11βHSD1 was demonstrated in an acute mouse adipose tissue explant model at doses of 5−50 mg/kg with significant inhibition after 8 h at the 15 and 50 mg/kg doses (36% and 39%, respectively). Evaluation of 17 in diet-induced obese (DIO) mice at doses of 25 and 50 mg/kg twice daily showed reduced fed blood glucose levels relative to vehicle after 2 weeks. On day 13, there were statistically significant decreases in insulin levels at both doses when compared with vehicle, and D



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Figure 6. 11β-HSD1 inhibitors reported by Merck.

nM). Low clearance (0.06 L h−1 kg−1, 1 mL min−1 kg−1) and high oral bioavailability (81%) in cynomolgus monkey allowed evaluation in an ex vivo model with dose dependent activity demonstrated at doses of 4, 20, and 100 mg/kg. Scientists at Merck have reported the identification of adamantyltriazole 29 (compound 544) from high throughput screening efforts (Figure 6). It has potency against the human enzyme (IC50 = 8 nM) and moderate potency in mouse (IC50 = 98 nM) with good selectivity over both human (IC50 > 3 μM) and mouse 11β-HSD2 (IC50 > 10 μM).54 Activity in vivo was demonstrated in mice following an oral dose of 10 mg/kg which inhibited the conversion of [3H]cortisone to [3H]cortisol at 1 and 4 h postdose (59% and 17% inhibition, respectively). Compounds such as 30 showed increased efficacy (85% and 47% inhibition, respectively) despite being less potent against the human (IC50 = 37 nM) and mouse (IC50 = 109 nM) isoforms, and this was attributed to improved pharmacokinetics. Compound 29 showed activity in a DIO mouse model when dosed twice daily at 20 mg/kg for 11 days, leading to a reduction in body weight (7%), cumulative food intake (12%), and fasting blood glucose levels (15%) relative to vehicle treated animals. In a high fat feeding, low dose streptozotocin (HF STZ) mouse model dosing twice daily at 30 mg/kg for 9 days resulted in lower fasting and postprandial glucose levels (37%) together with improved insulin sensitivity.55 Compound 29 dosed at 10 mg kg−1 day−1 in a high fat diet for 8 weeks also slowed plaque progression in an atherosclerosis (apolipoprotein E knockout) mouse model with lower accumulation (84%) of aortic total cholesterol as well as lower serum cholesterol and triglycerides.

The sulfonamide linker was subsequently replaced with a diarylsulfone,48 leading to compounds exemplified by 22 that showed improved metabolic stability and oral bioavailability while retaining potency against human (enzyme IC50 = 0.9 nM; cell IC50 = 11 nM) and cynomolgus monkey (enzyme IC50 = 3 nM). Compound 22 was orally bioavailable in rat (F = 55%), dog (F = 73%), and cynomolgus monkey (F = 13%). Efficacy was demonstrated in the ex vivo model described above at 2 and 10 mg/kg. Inversion of the sulfonamide linkage and optimization of both the aryl substitution and N-substituent led to the identification of a structurally distinct subseries typified by 23 which retained potency in an enzyme assay (IC50 = 1.4 nM) and cell assay (IC50 = 2.2 nM).49 Further exploration around the trifluoromethyl carbinol sulfonamides revealed that benzamides such as 24 were suitable isosteres for the sulfonamide and further optimization in relation to the pharmacokinetic profile resulted in compound 25.50 Although this exhibited activity in cynomolgus monkey ex vivo models, the compound exhibited in vitro cytotoxicity in HeLa cells (IC50 = 2.5 μM). Replacement of the transcyclohexyl-3-pyridyl substituent and optimization gave amide 26 which showed reduced cytotoxicity (IC50 > 10 μM) and low activation of PXR.51 Further efforts to remove PXR liability and to optimize protein binding related shifts in potency resulted in hydroxypiperidine 27.52 Subsequent optimization to increase potency led to primary amide 28 which was extremely potent against an enzyme (IC50 = 0.8 nM) and cellular (IC50 = 3 nM) endpoint.53 Cellular potency in the presence of 3% human serum albumin was reduced (IC50 = 37 nM), but the compound retained activity in an adipocyte (IC50 = 17 nM) assay and against the cynomolgus monkey enzyme (IC50 = 22 E



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Figure 7. 11β-HSD1 inhibitors reported by Pfizer.

Optimization of pharmacokinetics led to replacement of the adamantyl with substituted benzyl groups and two cyclopropyl substituents in place of the cycloheptyl ring, leading to 31.56 This compound was potent against both human (IC50 = 5 nM) and mouse 11β-HSD1 (IC50 = 16 nM) and had good efficacy in the pharmacodynamic model described above (91% inhibition after 4 h postdose). Mouse pharmacokinetics showed low clearance (11 mL min−1 kg−1), an extended half-life (1.5 h), and complete oral bioavailability (F ≈ 100%). Compound 31 was subsequently identified as MK-0916 and entered phase II trials in 2004.57 Further optimization of pharmacokinetics involved replacement of the adamantyl with aryl groups leading to compounds such as 32, which showed exquisite potency against both human and mouse (both IC50 < 1 nM) and extended efficacy in the pharmacodynamic model described above (74% inhibition 16 h postdose).58 Further work led to compound 33 which had high human and mouse potency (both IC50 < 1 nM), good selectivity over human 11β-HSD2 (IC50 > 4 μM), and pharmacodynamic activity (36% inhibition 16 h postdose).59 Notably and in contrast to other related compounds, 33 was devoid of PXR agonism. This was attributed to the judicious placement of polar functionality driven by molecular modeling of interactions with PXR.60 Hybridization of these structural motifs led to 34 which is potent against human (IC50 = 6 nM) and mouse (IC50 = 2 nM) and improved pharmacodynamic activity (80% inhibition 16 h postdose). Compound 34 has low clearance (5 mL min−1 kg−1), an extended half-life (7 h), and high oral bioavailability (F = 96%) in mouse pharmacokinetic studies. PXR activation was low (23% activation at 10 μM), and the compound had a favorable CYP450 profile (3A4, 2C9, and 2D6, all IC50 > 20 μM).61 Merck have also disclosed a series of bicyclo[2.2.2]octyltriazoles and the medicinal chemistry involved in evolving 35 to trifluoromethyl carbinol 36.62 Compound 36 is potent against both human (IC50 = 1 nM) and mouse (IC50 < 1 nM) and exhibits good pharmacodynamic activity (84% inhibition 16 h postdose). Work on understanding the site of metabolism on the alkyl chain led ultimately to the sulfone 37.63 This compound is potent against both human (IC50 = 3 nM) and mouse (IC50 = 2 nM) 11β-HSD1 with good selectivity over 11β-HSD2 (both species IC50 > 4 μM). Compound 37 demonstrated good pharmacodynamic activity (63% inhibition 16 h postdose) and was subsequently identified as MK-0736, which entered phase II trials in 2005.57

By combination of structural features of known 11β-HSD1 inhibitors, examples of azabicylic sulfonamides such as 38 and 39 were also derived.64 These compounds have reasonable potencies against human (IC50 = 40 nM and IC50 = 37 nM, respectively) but are more potent against the mouse isoform (IC50 = 1 nM and IC50 = 5 nM, respectively). Researchers at Pfizer have described optimization in terms of ligand efficiency and physiochemical properties of an initial lead sulfonamide 40 into the development compound 41 (PF915275) (Figure 7).65 Compound 41 is very potent against human 11β-HSD1 in an enzyme assay (Ki < 1 nM) but less so in mouse (Ki = 750 nM) and rat (hepatoma cell IC50 = 14 500 nM), which prevented demonstration of biomarker inhibition or efficacy in rodent models. Potency determinations across species in hepatocytes indicated that monkey (IC50 = 100 nM) and dog (IC50 = 120 nM) were more similar in activity to human (IC50 = 20 nM). Human potency was maintained in a HEK393 cellular assay (IC50 = 5 nM), and the compound showed no activity against 11β-HSD2 (50%) in three preclinical species (mouse, rat, and dog). A 31-day study in DIO mice showed reduction in glucose (fed, −19%; fasting, −15%) and insulin (fed, −44%; fasting, −33%) levels at a dose of 0.3 mg compound per gram of diet. G



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Figure 10. 11β-HSD1 inhibitors reported by Abbott.

lipophilicity led to benzoic acid 55 (AZD8329).78 This compound is a potent inhibitor of human (IC50 = 9 nM), rat (IC50 = 86 nM), and dog (IC50 = 8 nM) 11β-HSD1 but is much less potent against mouse (IC 50 = 6.1 μM). Pharmacokinetics remained good for three preclinical species (F > 40%), and the amount of glucuronide formed across species in hepatocytes was minimal representing a minor route relative to oxidative metabolism pathways. Pharmacodynamic effects were demonstrated in both liver and adipose in a rat ex vivo model at doses of 10 mg/kg. Evolution of a neutral series with good pharmacokinetic parameters has also been described involving a scaffold switch to pyrimidine, ultimately leading to hydroxyadamantylamide 56.79 Compound 56 has modest potency against human (IC50 = 102 nM) and mouse 11βHSD1 (IC50 = 95 nM) together with excellent bioavailability in both rat and dog (100%). Co-optimization of human and rodent potency represented a challenge for this series which was overcome using a combination of Free−Wilson and structural approaches leading to neutral pyrimidine 57.80 This compound was potent against human (IC50 = 31 nM) and mouse (IC50 = 32 nM) with no activity against 11β-HSD2 (IC50 > 10 μM). Pharmacokinetics were characterized by moderate clearance in mouse (57 mL min−1 kg−1) and rat (9 mL min−1 kg−1) given the high free drug levels (>30% free) of this compound and reasonable oral bioavailability in mouse (34%) and rat (61%). An ex vivo adipose model in mouse investigating the PK/PD response of 57 allowed determination of an in vivo IC50 in close agreement (50 nM) with the in vitro determination demonstrating target engagement and giving confidence that free drug concentration in plasma was a good surrogate for concentration in adipose. Glucose and body weight efficacy in a mouse disease model were demonstrated for 57 at high doses (300 mg kg−1 day−1) but only body weight efficacy at lower doses (50 mg kg−1 day−1) despite proven target engagement in the liver. A recent report describes the

structure guided optimization of a series of azetidin-2-ones from initial hit 58, derived from high throughput screening, to compound 59.81 This compound had potency against both human (IC50 = 74 nM) and mouse (IC50 = 350 nM) forms of the enzyme and was orally bioavailable in mice (F = 22%) with moderate clearance (42 mL min−1 kg−1). Abbott has reported optimization of a dichloroaniline high throughput screening hit 60 into 61 with human (Ki = 22 nM) and rat (Ki = 39 nM) potency (Figure 10).82 An alternative butyrolactam hit 62 was elaborated leading to the identification of a trans-1,4-adamantylamide as a hydrophobic, yet metabolically stable group. Lactam 63 showed good potency in human (IC50 = 3 nM) and mouse (IC50 = 2 nM) and was shown to inhibit enzyme in both liver and fat in an ex vivo model as well as to have activity in a DIO model.83 Improvements to the synthesis of 63 were subsequently reported.84 An adamantyl hit 64 was also optimized with regard to improving metabolic stability resulting in the trans-1,4adamantyl alcohol 65.85 Substitution at the α-position to the carbonyl with a geminal dimethyl group and a shift to a trans1,4-adamantylamide group gave 66, which was potent against human (Ki = 9 nM) and mouse (Ki = 5 nM) with improved metabolic stability relative to 65.86 A description of the synthesis of 66 on a kilogram scale has been reported,87 and this compound has subsequently been identified as ABT-384, which is currently in trials for Alzheimer’s disease.88 Further work around the related adamantylamide 67, identified during a program of hit to lead work, led to reports of replacements for the adamantyl group such as bicyclo[2.2.2]octane 68.89 Efforts to improve the pharmacokinetic and pharmacodynamic profiles resulted in a number of heterocyclic replacements for the amide on the adamantyl as well as more optimal heteroaryl groups such as the pyrazole pyridine ether 69.90 Attempts to extend from the adamantylamide led to the identification of secondary amides such as 70 that were potent H



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Figure 11. 11β-HSD1 inhibitors reported by Bristol-Myers Squibb.

mouse, attributed to acyl glucuronidation, prevented further progression of this chemotype. Researchers at Vitae Pharmaceuticals have described the use of structure based design to generate an adamantylurea 81 which was optimized in terms of potency, selectivity, and physical properties to compound 82 (Figure 12).98 The

and selective inhibitors, but because of lower metabolic stability, it was concluded that the primary amide was optimal at this position.91 Sulfones and sulfonamides were investigated, and following optimization of the aryl ring, the sulfone 71 was identified as a potent inhibitor of both human (Ki = 6 nM) and mouse (Ki = 3 nM) forms of the enzyme. Pharmacokinetic profiles of 71 in mouse (F = 100%) and monkey (F = 109%) were excellent, and the compound was shown to inhibit 11βHSD1 in liver, fat, and brain tissue up to 16 h postdose in an ex vivo DIO mouse model at a dose of 30 mg/kg.92 Bristol-Myers Squibb has optimized a piperidineamide high throughput screening hit 72 of moderate potency (IC50 = 235 nM) into a series of chemotypes that are extremely potent against the enzyme (e.g., IC50 = 0.1 nM for compound 73; IC50 = 7.2 nM for compound 74) as shown in Figure 11.93 Compound 74 was further developed into a 1,2,4triazolopyridine series, and examples such as 75 have shown high potency against human 11β-HSD1 (IC50 = 12 nM) although these were less potent against mouse 11β-HSD1 (IC50 = 1026 nM).94 Compound 75 showed some activity against human 11β-HSD2 (IC50 = 2.52 μM) but little activation of the PXR receptor (EC50 >50 μM) in contrast to other members of this series lacking polar functionality which displayed partial to full activation of PXR (EC50 of 0.15−3 μM). Further work on this series led to the identification of a clinical candidate 76 (BMS-770767), which has been progressed into trials.95 A structurally distinct hydroxypyrimidine high throughput screening hit 77 was optimized through a strategy of core cyclization to give compounds such as 78 that had potency against human (IC50 = 12 nM) and mouse (IC50 = 105 nM) forms of the enzyme.96 With this compound, the phenol forms an interaction with the key residues (Ser170 and Tyr183) in the active site of the enzyme. Glucuronidation in human liver microsomes and weak cellular activity represented a key challenge to the progression of this series. An alternative starting point was the adamantylacetic acid 79 which was optimized into the acid 80 that demonstrated potency against both human (IC50 = 3 nM) and mouse (IC50 = 184 nM) isoforms of the enzyme.97 This chemotype is unusual in that the acid functionality is postulated to interact with the key residues (Ser170 and Tyr183). Low plasma exposure in

Figure 12. 11β-HSD1 inhibitors reported by Vitae Pharmaceuticals.

compound was potent against human 11β-HSD1 enzyme (IC50 = 1.1 nM) and adipocytes (IC50 = 2.5 nM) and was selective against 11β-HSD2, 3β-HSD2, and 17β-HSD1 (all IC50 > 10 μM). Lipophilicity was moderate (log D7.4 = 3.1), and the compound showed no inhibition of CYP3A4, CYP2C9, and CYP2D6 (IC50 > 15 μM) and did not have significant binding or activity against a panel of 68 receptors and ion channels. The sodium salt of 82 had good pharmacokinetics in rat with moderate clearance (27 mL min−1 kg−1) and good oral bioavailability (90%) but had more moderate oral bioavailability in mice (29%) and monkey (31%). In mice dosed orally with 82 (30 mg/kg), concentrations were higher (18-fold) in liver and lower in adipose (0.3-fold) relative to plasma levels. In a cynomolgus monkey study, oral dosing of compound 82 (10 mg/kg) was shown to reduce the plasma cortisol concentration (−80%) consistent with inhibition of 11β-HSD1. The I



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Figure 13. 11β-HSD1 inhibitors reported by Shanghai Institute of Materia Medica.

HSD1 (IC50 = 2 nM) with no activity against 11β-HSD2.104 A 23-day study in ob/ob mice dosed by intraperitoneal injection (50 mg kg−1 day−1) showed improved glycemic control, decreased serum lipids, and enhanced insulin sensitivity. Further work demonstrated that the phenyl ring could be replaced with heterocycles such as thiazole 89 which retained potency against human 11β-HSD1 (IC50 = 6 nM) but were less active against mouse (IC50 = 307 nM).105 Cyclization of the sulfonamide substituent and a switch from amide to urea led to the identification of 90 which was a weaker inhibitor of human 11β-HSD1 (IC50 = 21 nM) but more potent against mouse (IC50 = 0.4 nM).106 A 20-day study in ob/ob mice dosed by intraperitoneal injection (50 mg kg−1 day−1) showed average reductions in fasting (−31%) and nonfasting (−26%) glucose levels. Poor rodent pharmacokinetics and reduced levels of selectivity against human 11β-HSD2 (IC50 = 860 nM) represented challenges for this series. An alternative approach began with a scaffold hop from Biovitrum sulfonamide 5 leading to amide 91 which was optimized to bornylamide 92.107 This was potent against both human (IC50 = 0.4 nM) and mouse (IC50 = 18 nM) and showed short acting inhibition of 11β-HSD1 in an ex vivo mouse model after oral dosing. Alternative piperidineamide scaffolds were also found to be active, with hydroxyladamantylamide 93 being potent against human (IC50 = 1.2 nM) and mouse (IC50 = 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.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 (IC50 = 3.3 nM); however, mouse potency was significantly reduced ( 10 μM) and had no activity against CYP2C9 or CYP2D6 (IC50 > 30 μM). Rat pharmacokinetics showed moderate clearance (42 mL min−1 kg−1) and oral bioavailability (42%). Structure based design was used to identify cyclic carbamate 85 that was optimized in terms of potency to give 86.100 Compound 86 was potent against the human enzyme (IC50 = 0.8 nM) and in human adipocytes (IC50 = 2.5 nM) but was less potent against the enzyme in the presence of 50% human plasma (18-fold). This is consistent with the compound being highly (>99%) protein bound in dog, monkey, and human plasma. The compound had weak activity against 3β-HSD2 (IC50 = 4.7 μM) and CYP2C9 (IC50 = 4.9 μM) but no activity against 11β-HSD2 or 17βHSD1 (both IC50 > 10 μM) and no activity against CYP2C9 or CYP2D6 (IC50 > 30 μM). Compound 86 had a favorable overall selectivity profile (>5000-fold selective) against a panel of 165 enzymes and receptors and showed no inhibition of the hERG ion channel (IC50 > 10 μM). Oral bioavailability was high in rat (94%) with lower values measured in dog (16%) and monkey (26%). Potency against the mouse isoform was significantly lower (IC50 = 670 nM), but 86 remained potent in cynomolgus monkey (IC50 = 1 nM) and was subsequently shown to reduce cortisol production in vivo (−85%) at a dose of 10 mg/kg. An approach of structure-based virtual screening was used by researchers at the Shanghai Institute of Materia Medica to identify a sulfonamide starting point 87 (Figure 13).101−103 Optimization of the amide substituent led to the identification of 88, which was equipotent against human and mouse 11βJ



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and a bioavailability of 32%. Activity was demonstrated in an ex vivo cynomolgus monkey model at a dose of 20 mg/kg with 11β-HSD1 inhibition in fat (62%) and liver (57%) tissues after 2 h. Oral dosing of 100 in KKAy mice at 100 mg/kg for 18 days demonstrated reduction of nonfasting blood glucose (−28%) relative to vehicle, and an OGTT showed a reduction in AUC (−18%) relative to vehicle. A further focus on adamantyl containing compounds led to the identification of cyclic sulfamide 101.115 Optimization with respect to potency and metabolic stability led to the identification of 102 which was potent against human (IC50 = 1 nM) and mouse (IC50 = 2 nM) 11β-HSD1. The compound was devoid of CYP activity (five isoforms, >100 μM) and was weakly active against hERG (IC50 = 37 μM). Rat pharmacokinetics showed moderate clearance (0.7 L h−1 kg−1, 12 mL min−1 kg−1) and good bioavailability (69%). Activity was demonstrated in an ex vivo mouse model with inhibition in fat of 11β-HSD1 (96%) at a dose of 20 mg/ kg and in an ex vivo cynomolgus monkey model (>80%) in three fat tissues at a dose of 10 mg/kg. Further work on the desmethyl analogue 103 (KR-67183), which had similar human (IC50 = 1 nM) and mouse (IC50 = 4 nM) potency, demonstrated improved glucose tolerance and insulin sensitivity in a DIO mouse model at doses of 20 and 50 mg kg−1 day−1.116 No effects on the adrenal weight to body weight ratio or plasma corticosterone levels were observed suggesting that no activation of the HPA axis was occurring. This group has also reported the development of a three-dimensional quantitative structure−activity relationship (3D-QSAR) model based on molecular docking.117 A team at Merck-Serono identified the carboxylic acid hit 104 from a high-throughput screen and optimized it with regard to a binding efficiency index to pentanedioic acid diamide 105 (Figure 15).118 The compound was active against

by the structure of Pfizer prolinamide 45 together with optimization led to hydroxyladamantylamide 95. This compound showed similar potency against human (IC50 = 7.7 nM) and mouse (IC50 = 11 nM) forms of the enzyme. 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.110 Efforts to develop an inhibitor of 11β-HSD1 that also activates PPARγ have been reported by structural hybridization of Biovitrum sulfonamide 5 with known PPARγ agonists.111 Compound 96 showed weak inhibition of mouse 11β-HSD1 (IC50 = 710 nM) and activation of human PPARγ (EC50 = 6620 nM). Rat pharmacokinetics were characterized by low clearance (2.8 mL min−1 kg−1) and complete bioavailability (100%). Blood glucose levels were reduced (−34%) after 4 weeks of dosing (20 mg/kg) in KKAy mice comparable to the effect of rosiglitazone (−39%) at a dose of 10 mg/kg. In an MSG rat model, compound 96 dosed at 10 mg/kg for 6 weeks showed a reduction in total fat mass (−12.5%) in contrast to rosiglitazone which showed an increase. A cyclic sulfonamide hit 97 was identified by researchers at the Korea Research Institute of Chemical Technology from high-throughput screening (Figure 14).112 Exploration in this

Figure 14. 11β-HSD1 inhibitors reported by Korea Research Institute of Chemical Technology.

series led to the identification of 98 (KR-66344) which was potent against human 11β-HSD1 (IC50 = 31 nM) but was a much weaker inhibitor in mouse (IC50 = 7.8 μM). The compound showed good selectivity against hERG (IC50 > 100 μM) and 11β-HSD2 (6% inhibition at 20 μM) and had acceptable pharmacokinetics in rat with low clearance (0.4 L h−1 kg−1, 7 mL min−1 kg−1) and good bioavailability (49%). Subsequent work demonstrated that 98 was effective in reducing plasma glucose levels (−27%) in an OGTT in ob/ ob mice after 5 days of dosing at 200 mg kg−1 day−1.113 Beneficial changes were also observed in plasma lipid profiles. An alternative hit 99 based on a search of adamantyl containing compounds was optimized to thiazolidine amide 100 which was equipotent against human and mouse 11β-HSD1 (IC50 = 3 nM).114 This compound showed no activity against hERG or 11β-HSD2 and had a reasonable pharmacokinetic profile in rat with moderate clearance (2.9 L h−1 kg−1, 48 mL min−1 kg−1)

Figure 15. 11β-HSD1 inhibitors reported by Merck-Serono.

human 11β-HSD1 (IC50 = 8 nM) but less potent against mouse (IC50 = 88 nM) or rat (IC50 = 980 nM). No activity against 11β-HSD2 (IC50 >10 μM) was observed. In terms of pharmacokinetics, the compound had moderate clearance in rat (1.8 L h−1 kg−1, 30 mL min−1 kg−1) leading to modest bioavailability (F = 30%). A second series of spirocyclic carboxamides was also identified from high-throughput screening, and the optimization of hit 106 to lead 107 has also been reported.119 Amide 107 is very potent against human 11βHSD1 (IC50 = 0.5 nM) but much less so against the mouse enzyme (IC50 = 377 nM). An alternative pyrrolidineamide 108 was also obtained via high-throughput screening and optimized to the 7-azaindole derivative 109.120 Potencies against the human (IC50 = 10 nM) and mouse (IC50 = 720 nM) forms of K



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Figure 16. 11β-HSD1 inhibitors reported by Sanofi.

the enzyme have been reported with no observable 11β-HSD2 activity (IC50 > 10 μM). Disappointingly 109 showed high clearance in rats (4.0 L h−1 kg−1, 67 mL min−1 kg−1), leading to poor bioavailability (F < 5%). High-throughput screening of the Sanofi compound collection led to the identification of urea 110 as a potential starting point (Figure 16).121 Optimization guided by X-ray structural information gave pyrrolidineurea 111 which allowed ex vivo mouse efficacy to be demonstrated in both fat and liver.121 Issues with CYP3A4 inhibition observed with this compound were overcome by replacing the pyrrolidine pyrazole with an adamantyl group, and subsequent rounds of optimization led to the identification of compound 112 (SAR184841) as a clinical candidate.122 Compound 112 is a potent inhibitor of human (IC50 = 4 nM), mouse (IC50 = 6 nM), and rat (IC50 = 7 nM) 11β-HSD1 and exhibits only moderate inhibition of 11β-HSD2 (IC50 = 4 μM). The compound was selective against hERG (IC50 > 10 μM) and showed no CYP3A4 inhibition (IC50 > 50 μM) or induction and no evidence of mutagenicity or teratogenicity in vitro. In terms of rat pharmacokinetics, the compound is characterized by high clearance (5.2 L h−1 kg−1, 87 mL min−1 kg−1) and a high volume of distribution (14 L/kg), leading to moderate bioavailability (F = 25%). A 4-week study in DIO mice, at doses of 1, 3, or 10 mg kg−1 day−1, showed dose-dependent reductions of plasma glucose and insulin, together with improvement in other parameters such as leptin and cholesterol. An OGTT after 3 weeks showed significant reduction in AUC (−23%) at a dose of 10 mg/kg. No effects on body weight or food intake were observed, and no modification of an HPA axis biomarker (corticosterone) was reported. A structurally distinct series was identified from highthroughput screening involving identification of an impurity 113 present in a hit sample. This was optimized with respect to potency and metabolic stability to afford 114 which showed good potency against human 11β-HSD1 (IC50 = 7 nM) but was less potent against mouse (IC50 = 199 nM).123 The medicinal chemistry evolution of high-throughput phenol screening hit 115 to perhydroquinolylbenzamide 116 has been reported by Novartis (Figure 17).124 Compound 115 has modest potency against human 11β-HSD1 (IC50 = 100 nM) and showed in vivo efficacy in an adrenalectomized mouse model with a reduction of liver corticosterone levels of 73%. Optimization of an azepine amide high throughput screening hit 117 to sulfonamide 118 was reported by a group at Schering-Plough (Figure 18). Compound 118 was potent

Figure 17. 11β-HSD1 inhibitors reported by Novartis.

against human (IC50 = 3 nM) but less active against mouse (IC50 = 57 nM).125

Figure 18. 11β-HSD1 inhibitors reported by Schering-Plough.

Using a pharmacophoric analysis of the X-ray structures of known ligands, researchers at Toray generated a sevenmembered ring lactam 119 scaffold which was subsequently optimized to 120 (Figure 19).126 Compound 120 was potent

Figure 19. 11β-HSD1 inhibitors reported by Toray.

against human (IC50 < 3 nM) and mouse (IC50 = 35 nM) 11βHSD1 and showed comparable efficacy to pioglitazone in terms of reduction of fasting blood glucose in a DIO mouse model. Researchers at the University of Edinburgh have reported an adamantyl hit 121 identified from an in silico screen (Figure 20). This compound showed equivalent potency against both the human (IC50 = 82 nM) and mouse (IC50 = 81 nM) isoforms of the enzyme.127 Compound 121 showed inhibition of 11β-HSD1 in liver (63%), fat (54%), and brain (39%) when dosed at 10 mg/kg in an ex vivo pharmacodynamic model with no inhibition of 11β-HSD2 in the kidney. A tetrazole hit 122 was also identified and optimized to give ketone 123. This compound showed potency against the human enzyme (IC50 = L



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Figure 21. 11β-HSD1 inhibitors reported by University of Bath. Figure 20. 11β-HSD1 inhibitors reported by The University of Edinburgh.

nM).138 Work on alternatives to the adamantyl group led to aryl ketones exemplified by 134 which were less potent (IC50 = 138 nM).139 The authors note that the ketone series (131− 134) have the potential to be substrates for the enzyme in a similar way to that reported by Wyeth71 but comment that they have not tested this hypothesis. Researchers from the University of Innsbruck have also reported an approach toward the identification of 11β-HSD1 inhibitors using common feature pharmacophore modeling and virtual screening.140 Synthesis around a virtual hit 135 led to the identification of piperazinesulfonamide 136 as a weak inhibitor (IC50 = 700 nM) (Figure 22).141

114 nM); however, metabolite stability data indicated that the ketone functionality was being reduced and that this compound may be acting as a substrate rather than an inhibitor.128 This is in accordance with reports from Wyeth on a series of ketosulfonamides that also acted as substrates for 11βHSD1.71 A structurally distinct inhibitor 124 (UE-1961) has been reported to have potency in a HEK293 cell assay against human (IC50 = 479 nM), rat (IC50 = 287 nM), and mouse (IC50 = 528 nM) isoforms of 11β-HSD1.129 This compound was demonstrated to improve spatial memory performance in aged mice using a Y-maze assessment. On the basis of overlays of disclosed 11β-HSD1 inhibitors, inhibitors such as 125 were developed in combination with a group at the Universidad Autónoma del Estado de Morelos.130 Compound 125 showed weak activity in a HEK293 cell assay (38% at 10 μM) but displayed in vivo antidiabetic activity using an STZ-nicotinamide rat model of diabetes at 100 mg/kg intragastric administration (78% reduction of glucose excursion relative to control). These groups have also reported the tetrazole derivative of clofibric acid 126 as a weak inhibitor of 11β-HSD1 (51% at 10 μM) which demonstrated glycemic lowering in the model described above at a dose of 50 mg/ kg.131 A group from the University of Bath have described the identification of a sulfonamide benzothiazole 127 that has weak activity in a human HEK293 cell assay (IC50 = 3.2 μM) as shown in Figure 21. 132 A structurally related amide benzothiazole 128 had similar activity (IC50 = 3.2 μM).133 A more potent series of adamantylamides exemplified by compound 129 was also identified (IC50 = 229 nM).134 Optimization of this scaffold resulted in compounds such as 130 where the adamantyl ring has been replaced with a substituted benzyl group with only a modest reduction in potency (IC50 = 280 nM).135 A series of adamantyl ethanone derivatives such as 131 with increased potency (IC50 = 56 nM) have been described.136 Replacement of the substituted phenyl with heterocycles led to compounds such as pyridine 132 that were more potent in a HEK293 cell assay (IC50 = 34 nM).137 Further optimization on this series led to thio-linked heterocycles such as triazole 133 that were more potent (IC50 = 19

Figure 22. 11β-HSD1 inhibitors reported by University of Innsbruck.

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CLINICAL TRIALS Compound 41 was progressed into phase I trials by Pfizer in 2006 with 60 healthy adult volunteers over 14 days.142 The compound was well tolerated over the dose range given (0.3− 15 mg once daily). In terms of pharmacokinetics, 41 was rapidly absorbed (median Tmax = 1 h) and slowly eliminated (mean t1/2 = 30 h) with clearance values in the range of 1.0−1.4 L/h (16−23 mL/min). Less than 1% of the dose was excreted unchanged in the urine, indicating no significant renal elimination. Dose-proportional increases in exposure were observed, and steady state levels were obtained by day 7. In terms of pharmacodynamics, 41 dose-dependently inhibited conversion of prednisone to prednisolone (maximum of 37% inhibition at the top 15 mg dose). It also dose-dependently reduced the (5α- + 5β-tetrahydrocortisol) to tetrahydrocortisone ratio (maximum reduction of 26% after 14 days). The free cortisol to cortisone ratio in urine did not change and no clinical signs of hypertension or hypokalemia were observed consistent with no significant inhibition of 11β-HSD2. Levels of ACTH, adrenal androgens, and the urinary corticosteroid profile were monitored to assess any activation of the HPA axis, but these were not significantly altered. In 2007 it was M



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than 11β-HSD1 inhibition.57 According to the Merck company Web site, compounds 31 and 37 are no longer in the pipeline portfolio, suggesting that they are not currently in active development. Compound 17 has been progressed by Amgen into a phase I study of healthy, obese individuals in an attempt to derive a pharmacokinetic/pharmacodynamic relationship at doses of 3− 300 mg.148 Values for an IC50 (0.975 ng/mL) and maximal inhibition (Imax = 1.19 ng/mL) of enzyme in adipose tissue were derived. Inhibition of enzyme was sustained over a 24 h period as measured by ex vivo adipose samples. An offset between plasma and adipose concentrations was noted, and this was attributed to perfusion limited distribution of compound to adipose tissue. This compound was discontinued from development in 2011 for undisclosed reasons according to a press release from Amgen.42 At the time of writing, other compounds such as compound 76 (Bristol-Myers Squibb) and BI-135585 (Vitae/Boehringer Ingelheim, structure not disclosed)149 are reported to be in clinical development for the treatment of diabetes. However, a number of other companies have been unsuccessful in progressing 11β-HSD1 inhibitors beyond phase II trials. JTT654 (Japan Tobacco, structure not disclosed) reached phase II trials in 2009 before reportedly being discontinued from development.150 RG-7234 (Roche, structure not disclosed) completed phase I trials in 2009 but was reported discontinued in 2010.151 A further compound RG-4929 (Roche, structure not disclosed) reached phase II trials in 2011 but was discontinued according to a company presentation in 2012.152 In addition to treatment of diabetic patients, this compound was also investigated in patients with nonalcoholic fatty liver disease. LY-2523199 (Lilly, structure not disclosed) entered phase II in 2011 but is no longer in active development according to a company report published in July 2013.153 Compound 50 (Wyeth) completed phase I trials in 2008 but does not appear to have progressed further. Similarly, BMS816336 (Bristol-Myers Squibb, structure not disclosed) completed phase I trials in 2009, but no further development has been reported.154 Compound 53 (AstraZeneca) reached phase II trials for the treatment of raised intraocular pressure in 2011, but development was halted according to a company pipeline report in 2012. Compound 55 (AstraZeneca) completed phase I trials in 2010. Both 53 and 55 were considered safe and well tolerated, but neither was evaluated for efficacy in patients with type II diabetes, and no development activity is currently reported.155 Clinical trials are ongoing for other potential indications of 11β-HSD1 inhibitors including Alzheimer’s disease where 66 (Abbott) and UE-2343 (University of Edinburgh, structure not disclosed) are being evaluated.156 The utility of 11β-HSD1 inhibition in the treatment of glaucoma is also being investigated with HPP-851 (High Point Pharmaceuticals, structure not disclosed) currently in phase I trials.157

announced that this compound had progressed to phase II; however, it was subsequently stopped because of issues with tablet formulation.143 INCB-13739 (structure not disclosed) completed phase I trials in 2006 and was progressed into phase II trials in 2007 by Incyte.144In patients with type II diabetes, a dose of 200 mg in addition to metformin monotherapy resulted in significant reductions in HbA1C (−0.6%), fasting plasma glucose (−24 mg/dL), and homeostasis model assessmentinsulin resistance (HOMA-IR) (−24%) compared with placebo. Some reduction in body weight (up to 1 kg) and reductions in cholesterol (total and low density lipoprotein) and triglycerides in hyperlipidemic patients were observed. The drug was well tolerated, although a dose-dependent elevation in ACTH levels, potentially indicative of HPA axis activation, was observed. This was reversible, and basal cortisol homeostasis, testosterone in men, and free androgen index in women were unchanged. A subsequent commentary145 noted that efficacy was only observed at doses in excess of 100 mg despite a high potency (IC50 = 1.1 nM) in humans. The authors postulated that maximal inhibition of the enzyme (e.g., cover of the IC90 rather than IC50) may be required for efficacy. Adipose tissue distribution and increased splanchnic cortisol exposure were discussed in the context of the observation that efficacy was more evident in obese patients (BMI > 30 kg/m2). The size of elevation (2-fold) and reversibility of ACTH levels observed led the authors to postulate that this represented the maximal degree of HPA axis activation. A structurally distinct, potential back-up compound INCB-20817 (structure not disclosed) completed phase I clinical trials in 2008; however, this molecule no longer appears on the company pipeline and is presumed to no longer be in active development. Compound 31 was progressed into a 12-week phase IIa study in 2008 by Merck in patients with type II diabetes and metabolic syndrome.146 At dose ranges of 0.5−6 mg/day the compound was well tolerated but showed no significant improvement in fasting plasma glucose compared with placebo. Some modest and dose-dependent decreases in both blood pressure and body weight were observed together with a small but significant reduction of hBA1c (−0.3%). At 6 mg/day, an unexpected increase (10.4%) in low-density lipoprotein cholesterol (LDL-C) was observed compared with placebo. This was tentatively attributed to CYP3A4 induction, a known effect of this compound. Increases in circulating adrenal androgens (20−30%) were also observed, indicative of modest HPA axis activation, but within normal physiological levels. A subsequent 12-week study in 2008 of 31 and 37 in overweight and obese patients with hypertension has also been reported.147 The compounds were well tolerated but at the maximal dose (7 mg) 37 did not demonstrate statistically significant reduction in trough sitting diastolic blood pressure. Some encouraging effects on metabolic parameters were observed with decreases in both LDL-C (−12.3%), HDL-C (−6.3%), and body weight (−1.4 kg). Adrenal androgens elevation was also reported, but these were within 2-fold of normal physiological levels and not viewed as being clinically meaningful. A recent report from Merck seeking to understand the origin blood of blood-pressure-lowering effects observed in humans investigated the phenomena in mice. Similar exposures and observations were obtained in both wild-type and 11β-HSD1 knockout mice, leading the researchers to conclude that these effects were attributable to an unknown off-target activity rather

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SUMMARY AND CONCLUSIONS The work described above represents over a decade of intensive research by the medicinal chemistry community into developing inhibitors of 11β-HSD1. Various structurally diverse chemotypes have been reported and optimized to produce potent and selective inhibitors. The majority of reported inhibitors are neutral, with a small number of acidic examples and few bases. Inhibitors reported to date where the binding mode has been determined all have a structural feature that N



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mimics the carbonyl of the cortisone substrate and interacts with either or both of the key residues Ser170 and Tyr183. The most common structural classes exemplified are amides (together with ureas and carbamates), sulfonamides (together with sulfamides), and triazoles (and other heterocycles). Interestingly, ketone containing compounds have been identified as leads by some groups but have been shown in some cases to be substrates of the enzyme rather than inhibitors. Polycyclic, lipophilic groups are a common motif among various classes of disclosed inhibitors with adamantyl, norbornyl, and bicyclo[2.2.2]octyl motifs all present in compounds that have progressed to the clinic. A majority of leads have been identified from high throughput screening of compound collections, although lately, rational design and pharmacophore mapping have played an increasing role. This has been facilitated by a wealth of available X-ray crystal structures of the enzyme in complex with various inhibitors. Selectivity over the related enzyme 11β-HSD2, which hampered the development of inhibitors such as carbenoxolone, has been demonstrated in a number of chemical series. The challenge of achieving potency against both human and mouse isoforms, which plagued early work in this area, has now been largely overcome in a range of chemotypes and has facilitated preclinical evaluation in animal models. X-ray crystal structures have been instrumental in this and in optimizing compounds to nanomolar levels of potency. Medicinal chemistry problems, such as PXR activation associated with CYP450 induction, have emerged in a number of diverse structural series. These have inspired some elegant solutions, such as the judicious placement of polar substituents in a way to remove the liability without compromising potency. A range of high quality compounds have now progressed to the clinic and allowed the effects of 11β-HSD1 to be evaluated. Compounds have generally been well tolerated and have shown beneficial effects on various parameters relevant to the metabolic syndrome. Up-regulation of the HPA axis in response to 11βHSD1 inhibition has not proved to be a clinically significant issue, although elevations in adrenal androgens have been observed by both Merck and Incyte. However, to date, no compounds have progressed beyond phase II, with a failure to demonstrate sufficient efficacy being the predominant cause of attrition. Recent reports that some of the effects observed clinically may be in part due to targets other than 11β-HSD1 have further complicated the development picture for this class of compounds. Additional compounds from several companies remain in active development, and the authors hope that an inhibitor will be progressed through trials, demonstrate efficacy, and subsequently prove to be a novel, safe, and effective therapy for patients with the metabolic syndrome or another unmet medical need.

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worked as a Chemistry Teacher in Kenya with Voluntary Services Overseas. In 2003 he joined AstraZeneca as a medicinal chemist and became a team leader in 2006 working on lead generation and optimization programs. His research interests are in oncology and metabolic disease targets. In 2012 he was awarded the Royal Society of Chemistry Capps Green Zomaya Award for medicinal chemistry. Frederick W. Goldberg received his M.Sc. from Cambridge University, U.K., in 2000, his Ph.D. at Imperial College London in 2004 with Alan Armstrong, and then a Fulbright scholarship to perform postdoctoral studies with Philip Magnus at the University of Texas at Austin. He returned to the U.K. in 2006 to join AstraZeneca as a medicinal chemist and became a team leader in 2009, working on lead generation and optimization programs in oncology and diabetes. His research interests include kinases, structure based design, compound collection enhancement, chemical biology, and metabolism. In 2013 he was awarded the European Federation for Medicinal Chemistry Prize for Young Medicinal Chemist in Industry. Andy V. Turnbull received his Ph.D. in Physiological Sciences from The University of Manchester, U.K., in 1993 with Dame Professor Nancy Rothwell. He conducted postdoctoral studies in the neuroendocrinology of stress and inflammation at the Peptide Biology Laboratories at the Salk Institute (La Jolla, CA, USA) before returning to the U.K. to continue this research at the Medical Research Council. In 1999 he joined AstraZeneca as a preclinical pharmacologist evaluating novel therapies for the treatment of obesity. Since then, he has worked in various cardiovascular areas (including diabetes) and has led a number of drug programs from preclinical to early clinical evaluation.

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ACKNOWLEDGMENTS Graeme Robb is thanked for the generation of Figure 3. ABBREVIATIONS USED 11β-HSD1, 11β-hydroxysteroid dehydrogenase type 1; 11βHSD2, 11β-hydroxysteroid dehydrogenase type 2; ACTH, adrenocorticotropic hormone; CYP, cytochrome P450; DIO, diet induced obesity; HDL, high density lipoprotein; HEK, human embryonic kidney; HOMA-IR, homeostasis model assessmentinsulin resistance; HPA, hypothalamic−pituitary− adrenal; LDL, low density lipoprotein; PPAR, peroxisome proliferator-activated receptor; PXR, pregnane X receptor; QSAR, quantitative structure−activity relationship

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REFERENCES

(1) Grundy, S. M.; Brewer, H. B., Jr.; Cleeman, J. I.; Smith, S. C., Jr.; Lenfant, C.; American Heart Association; National Heart, Lung, and Blood Institute.. Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation 2004, 109, 433−438. (2) Björntorp, P.; Rosmond, R. Obesity and cortisol. Nutrition 2000, 16, 924−936. (3) Wamil, M.; Seckl, J. R. Inhibition of 11β-hydroxysteroid dehydrogenase type 1 as a promising therapeutic target. Drug Discovery Today 2007, 12, 504−520. (4) Gathercole, L. L.; Lavery, G. G.; Morgan, S. A.; Cooper, M. S.; Sinclair, A. J.; Tomlinson, J. W.; Stewart, P. M. 11β-Hydroxysteroid dehydrogenase 1: Translational and therapeutic aspects. Endocr. Rev. 2013, 34, 525−555. (5) Fraser, R.; Ingram, M. C.; Anderson, N. H.; Morrison, C.; Davies, E.; Connell, J. M. C. Cortisol effects on body mass, blood pressure, and cholesterol in the general population. Hypertension 1999, 33, 1364−1368.

AUTHOR INFORMATION

Corresponding Author

*Phone: +44 (0)1625 232567. Fax: +44 (0)1625 516667. Email: [email protected]. Notes

The authors declare no competing financial interest. Biographies James S. Scott received his Ph.D. in Organometallic Chemistry from Strathclyde University, Scotland, in 1997 with Professor William Kerr and went on to do postdoctoral studies in total synthesis with Professor Steven Ley in Cambridge, U.K. From 2001 to 2002 he O



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(138) Su, X.; Vicker, N.; Thomas, M. P.; Pradaux-Caggiano, F.; Halem, H.; Culler, M. D.; Potter, B. V. L. Discovery of adamantyl heterocyclic ketones as potent 11β-hydroxysteroid dehydrogenase type 1 inhibitors. ChemMedChem 2011, 6, 1439−1451. (139) Pradaux-Caggiano, F.; Su, X.; Vicker, N.; Thomas, M. P.; Smithen, D.; Halem, H. A.; Culler, M. D.; Potter, B. V. L. Synthesis and evaluation of thiadiazole derivatives as inhibitors of 11βhydroxysteroid dehydrogenase type 1. MedChemComm 2012, 3, 1117−1124. (140) Schuster, D.; Maurer, E. M.; Laggner, C.; Nashev, L. G.; Wilckens, T.; Langer, T.; Odermatt, A. The discovery of new 11βhydroxysteroid dehydrogenase type 1 inhibitors by common feature pharmacophore modeling and virtual screening. J. Med. Chem. 2006, 49, 3454−3466. (141) Hofer, S.; Kratschmar, D. V.; Schernthanner, B.; Vuorinen, A.; Schuster, D.; Odermatt, A.; Easmon, J. Synthesis and biological analysis of benzazol-2-yl piperazine sulfonamides as 11β-hydroxysteroid dehydrogenase 1 inhibitors. Bioorg. Med. Chem. Lett. 2013, 23, 5397−5400. (142) Courtney, R.; Stewart, P. M.; Toh, M.; Ndongo, M. N.; Calle, R. A.; Hirshberg, B. Modulation of 11β-hydroxysteroid dehydrogenase (11βHSD) activity biomarkers and pharmacokinetics of PF-00915275, a selective 11βHSD1 inhibitor. J. Clin. Endocrinol. Metab. 2008, 93, 550−556. (143) The study stopped because of tablet formulation issues. No safety issues were involved in the termination decision. See http:// clinicaltrials.gov/ct2/show/NCT00427401. (144) Rosenstock, J.; Banarer, S.; Fonseca, V. A.; Inzucchi, S. E.; Sun, W.; Yao, W.; Hollis, G.; Flores, R.; Levy, R.; Williams, W. V.; Seckl, J. R.; Huber, R. The 11-β-hydroxysteroid dehydrogenase type 1 inhibitor INCB13739 improves hyperglycemia in patients with type 2 diabetes inadequately controlled by metformin monotherapy. Diabetes Care 2010, 33, 1516−1522. (145) Hollis, G.; Huber, R. 11β-Hydroxysteroid dehydrogenase type 1 inhibition in type 2 diabetes mellitus. Diabetes, Obes. Metab. 2011, 13, 1−6. (146) Feig, P. U.; Shah, S.; Hermanowski-Vosatka, A.; Plotkin, D.; Springer, M. S.; Donahue, S.; Thach, C.; Klein, E. J.; Lai, E.; Kaufman, K. D. Effects of an 11β-hydroxysteroid dehydrogenase type 1 inhibitor, MK-0916, in patients with type 2 diabetes mellitus and metabolic syndrome. Diabetes, Obes. Metab. 2011, 13, 498−504. (147) Shah, S.; Hermanowski-Vosatka, A.; Gibson, K.; Ruck, R. A.; Jia, G.; Zhang, J.; Hwang, P. M. T.; Ryan, N. W.; Langdon, R. B.; Feig, P. U. Efficacy and safety of the selective 11β-HSD-1 inhibitors MK0736 and MK-0916 in overweight and obese patients with hypertension. J. Am. Soc. Hypertens. 2011, 5, 166−176. (148) Gibbs, J. P.; Emery, M. G.; McCaffery, I.; Smith, B.; Gibbs, M. A.; Akrami, A.; Rossi, J.; Paweletz, K.; Gastonguay, M. R.; Bautista, E.; Wang, M.; Perfetti, R.; Daniels, O. Population pharmacokinetic/ pharmacodynamic model of subcutaneous adipose 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity after oral administration of AMG 221, a selective 11β-HSD1 Inhibitor. J. Clin. Pharmacol. 2011, 51, 830−841. (149) Bioavailability and Pharmacokinetics of BI 135585 XX Administered as Tablet with and without Food. (Study was completed in 2011.) http://clinicaltrials.gov/show/NCT01286571. (150) Development of JTT-654 was terminated according to a company pipeline report on Oct 28, 2010. See http://www.jt.com/ investors/results/S_information/pharmaceuticals/pdf/P.L.20101028_ E.pdf. (151) Roche presentation, October 14, 2010, slide 37. See http:// www.roche.com/irp3q10e.pdf. (152) Roche presentation, October 16, 2012, p 47. See http://www. roche.com/irp3q12e.pdf. (153) Lilly presentation 2Q 2013, page 12. See http://files. shareholder.com/downloads/LLY/2073248133x0x678669/d90dc9fada40-4bb3-82f6-02acaa752eb7/Q2_2013_Slides.pdf.

(154) Safety Study of BMS-816336 in Healthy Male Subjects. (Study was completed in 2011.) http://clinicaltrials.gov/show/ NCT00979368. (155) Details of the clinical trials may be found on the company Web site: http://www.astrazenecaclinicaltrials.com/. (156) A Phase I Study of Oral UE2343 in Healthy Subjects. (Study was completed in July 2013.) http://clinicaltrials.gov/show/ NCT01770886. (157) According to the company Web site, HPP851 is currently being evaluated in a phase 1b/2a study in patients with elevated intraocular pressure or primary open-angle glaucoma. See http://www. ttpharma.com/TherapeuticAreas/PrimaryOpenAngleGlaucoma/ HPP851/tabid/119/Default.aspx.

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Medicinal Chemistry of Inhibitors of 11Î²-Hydroxysteroid

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