Efficacious 11β-Hydroxysteroid Dehydrogenase Type I Inhibitors in the Diet-Induced Obesity Mouse Model

Wan, Zhengming; Chenail, Eva; Xiang, Jason; Li, Huan‐Qiu; Ipek, Manus; Bard, Joel; Svenson, Kristine; Mansour, Tarek S.; Xu, Xin; Tian, Xianbin; Suri, Vipin; Hahm, Seung; Xing, Yuzhe; Johnson, Christian E.; Li, Xiangping; Qadri, Ariful; Panza, Darrell; Perreault, Mylène; Tobin, James F.; Saiah, Eddine

doi:10.1021/jm900639u

Cited by 61 publications

(42 citation statements)

References 41 publications

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“…In mice with genetic or diet-induced obesity, selective HSD1 inhibitors normalized glucose levels (Lloyd et al, 2009;Wan et al, 2009). Similar effects of HSD1 inhibition have also been noted in humans (Rosenstock et al, 2010).…”

Section: Introductionsupporting

confidence: 55%

Acute Inhibition of 11β-Hydroxysteroid Dehydrogenase Type-1 Improves Memory in Rodent Models of Cognition

Mohler¹,

Browman²,

Roderwald³

et al. 2011

J. Neurosci.

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Mounting evidence suggests excessive glucocorticoid activity may contribute to Alzheimer's disease (AD) and age-associated memory impairment. 11␤-hydroxysteroid dehydrogenase type-1 (HSD1) regulates conversion of glucocorticoids from inactive to active forms. HSD1 knock-out mice have improved cognition, and the nonselective inhibitor carbenoxolone improved verbal memory in elderly men. Together, these data suggest that HSD1 inhibition may be a potential therapy for cognitive deficits, such as those associated with AD. To investigate this, we characterized two novel and selective HSD1 inhibitors, A-918446 and A-801195. Learning, memory consolidation, and recall were evaluated in mouse 24 h inhibitory avoidance. Inhibition of brain cortisol production and phosphorylation of cAMP response element-binding protein (CREB), a transcription factor involved in cognition, were also examined. Rats were tested in a short-term memory model, social recognition, and in a separate group cortical and hippocampal acetylcholine release was measured via in vivo microdialysis. Acute treatment with A-801195 (10 -30 mg/kg) or A-918446 (3-30 mg/kg) inhibited cortisol production in the ex vivo assay by ϳ35-90%. Acute treatment with A-918446 improved memory consolidation and recall in inhibitory avoidance and increased CREB phosphorylation in the cingulate cortex. Acute treatment with A-801195 significantly improved short-term memory in rat social recognition that was not likely due to alterations of the cholinergic system, as acetylcholine release was not increased in a separate set of rats. These studies suggest that selective HSD1 inhibitors work through a novel, noncholinergic mechanism to facilitate cognitive processing.

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Section: Introductionsupporting

confidence: 55%

Acute Inhibition of 11β-Hydroxysteroid Dehydrogenase Type-1 Improves Memory in Rodent Models of Cognition

Mohler¹,

Browman²,

Roderwald³

et al. 2011

J. Neurosci.

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“…This stemmed from the earlier observation of poor in vivo results from compounds possessing high liver ex vivo activity alone. 17 This finding is in line with the report that liver-specific overexpression of 11β-HSD1 in transgenic mice causes insulin resistance without obesity, 33 possibly indicating the importance of targeting 11β-HSD1 outside of the liver, particularly in the adipose. 15 Our earlier work taught us that the active site of 11β-HSD1 provides opportunities for both electrostatic and van der Waals interactions (e.g., 1 16 and 2 17 ).…”

supporting

confidence: 83%

“…The compounds also showed oral efficacy in the cortisone-induced hyperinsulinemia rat model 16 and in the diet-induced obesity (DIO) mouse model 17 (Figure 1). In the continuation of our 11β-HSD1 program, we are reporting on the discovery of our clinical development candidate 18a [HSD-621, (R)-3,3,3-…”

mentioning

confidence: 99%

Discovery of HSD-621 as a Potential Agent for the Treatment of Type 2 Diabetes

Wan

Chenail

et al. 2012

ACS Med. Chem. Lett.

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11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes the conversion of inactive glucocorticoid cortisone to its active form, cortisol. The glucocorticoid receptor (GR) signaling pathway has been linked to the pathophysiology of diabetes and metabolic syndrome. Herein, the structure−activity relationship of a series of piperazine sulfonamide-based 11β-HSD1 inhibitors is described. (R)-3,3,3-Trifluoro-2-(5-(((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-yl)sulfonyl)thiophen-2-yl)-2-hydroxypropanamide 18a (HSD-621) was identified as a potent and selective 11β-HSD1 inhibitor and was ultimately selected as a clinical development candidate. HSD-621 has an attractive overall pharmaceutical profile and demonstrates good oral bioavailability in mouse, rat, and dog. When orally dosed in C57/BL6 diet-induced obesity (DIO) mice, HSD-621 was efficacious and showed a significant reduction in both fed and fasting glucose and insulin levels. Furthermore, HSD-621 was well tolerated in drug safety assessment studies. KEYWORDS: 11β-hydroxysteroid dehydrogenase type I (HSD1), diet-induced obesity, type II diabetes, piperazine sufonamides G lucocorticoid hormones are key regulators of a wide range of biological processes such as the control of immune and stress responses as well as modulation of energy metabolism. Glucocorticoids (cortisol in humans and corticosterone in mice and rats) stimulate hepatic glucose production and suppress insulin-mediated glucose uptake in peripheral tissues (i.e., adipose and muscle). 11β-Hydroxysteroid dehydrogenase type I (11β-HSD1), 1−7 a reduced β-nicotinamide adenine dinucleotide phosphate (NADPH)-dependent enzyme, predominantly acts as a reductase in vivo, converting inactive, nonreceptor binding cortisone to active, receptor-binding cortisol in tissues such as liver, adipose, vasculature, brain, and macrophages. 8 The enzyme is a tetramer consisting of two dimers each with an independent active site. 8 It has been proposed that 11β-HSD1 reductase activity exists predominantly in metabolic tissues because of the increased ratio of NADPH to β-nicotinamide adenine dinucleotide phosphate (NADP) within the endoplasmic reticulum (ER) lumen and/or through direct interactions with NADPH-generating hexose-6-phosphate dehydrogenase (H6PDH), an enzyme that has been associated with cortisone reductase deficiency in humans. 9 Cortisone itself is generated by the action of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) with cortisol using NADP as a cofactor. 11β-HSD1 levels are highest in liver and adipose tissues as well as in the central nervous system, whereas 11β-HSD2 is mainly expressed in the kidney and colon. 10 The rationale for 11β-HSD1 as a therapeutic target for the treatment of diabetes and the metabolic syndrome is based on data from tissue-specific overexpression in transgenic mice 11,12 and mice 11β-HSD knockout experiments. 13,14 In addition, 11β-HSD1 activity in adipose tissue also correlates positively with body mass index (BMI), fat percentage, and fas...

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“…PK experiments were conducted with C57B6 mice at 2 mg/kg (iv) and at 10 mg/kg (for 23) or 30 mg/kg (for 19) (po). 33 Figure 8. Rat PK of selected aurora kinase inhibitors.…”

Section: ■ Saturated Heterocyclesmentioning

confidence: 99%

Mitigating Heterocycle Metabolism in Drug Discovery

2012

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In the past few decades, drug metabolism research has played an ever increasing role in the design of drugs. 1−3 In vitro metabolism assays 4 have become an integral part of the routine profiling of compounds made in drug discovery. 5 The data from these assays have allowed medicinal chemists to focus their efforts on compounds with improved metabolic stability. 6 Detailed metabolite identification studies are also done more routinely, which provide information on how to strategically replace or block metabolically labile sites. 7 Additionally, in vivo PK studies are regularly conducted in drug discovery, which helps to build in vitro−in vivo PK relationships. 4 The positive influence that these advances in PKDM sciences have had on drug discovery is reflected in the fact that fewer drug candidates fail in the clinic for PKDM related issues. 8 This suggests that medicinal chemists are successfully integrating the data generated by their PKDM colleagues into the design of compounds with fewer metabolic liabilities.Extensive data from metabolism studies have allowed medicinal chemists to develop general principles for reducing compound metabolism. These methods include, but are not limited to, reducing lipophilicity, altering sterics and electronics, introducing a conformational constraint, and altering the stereochemistry of their compounds. While no single method is able to solve every metabolic problem, these principles do give medicinal chemists guidance on how to improve the metabolic liabilities of their compounds. If the specific site of metabolism is known, medicinal chemists block the site, typically with a fluorine, or replace the metabolically labile group with a bioisostere. 9 While several authors have reviewed these techniques for reducing metabolism, 5,10,11 there is no review that summarizes different approaches to improving the metabolic stability of heterocycles. In this review, we summarize examples where changes were made at or near the heterocycle to improve metabolic stability. By summarizing these examples, we hope to provide a useful guide to medicinal chemists as they attempt to improve the metabolic profile of their own heterocyclic compounds.The majority of the examples that are included in this review came from searching the online open access database CHEMBL. 12 In addition to having pharmacology data on compounds from the medicinal chemistry literature, CHEMBL has over 120 000 points of data on the ADMET properties of compounds. With the help of the visualization software Spotfire, we were able to cull examples from the CHEMBL ADMET data that focused on heterocycles. We also identified examples from papers that cite leading reviews in the drug metabolism field 13−18 and were present in other recent reviews on drug metabolism. 19−22 The main criteria that we placed on the examples selected for this review was that the change made to improve metabolism had to occur at or near the heterocycle and nowhere else on the molecule. This allowed us to eliminate examples where a change made t...

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Efficacious 11β-Hydroxysteroid Dehydrogenase Type I Inhibitors in the Diet-Induced Obesity Mouse Model

Cited by 61 publications

References 41 publications

Acute Inhibition of 11β-Hydroxysteroid Dehydrogenase Type-1 Improves Memory in Rodent Models of Cognition

Acute Inhibition of 11β-Hydroxysteroid Dehydrogenase Type-1 Improves Memory in Rodent Models of Cognition

Discovery of HSD-621 as a Potential Agent for the Treatment of Type 2 Diabetes

Mitigating Heterocycle Metabolism in Drug Discovery

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