Discovery of SAR184841, a potent and long-lasting inhibitor of 11β-hydroxysteroid dehydrogenase type 1, active in a physiopathological animal model of T2D

Venier, Olivier; Pascal, Cécile; Braun, Alain; Namane, Claudie; Mougenot, Patrick; Crespin, Olivier; Pacquet, François; Mougenot, Cécile; Monseau, Catherine; Onofri, Bénédicte; Dadji-Faïhun, Rommel; Leger, Céline; Ben-Hassine, Majdi; Van-Pham, Thao; Ragot, Jean-Luc; Philippo, Christophe; Farjot, Géraldine; Noah, Lionel; Maniani, Karima; Boutarfa, Asma; Nicolaï, Eric; Guillot, Etienne; Pruniaux, Marie-Pierre; Güssregen, Stefan; Engel, C.K.; Coutant, Anne-Laure; Miguel, B. De; Castro, Antonio de

doi:10.1016/j.bmcl.2013.02.018

Cited by 11 publications

(5 citation statements)

References 36 publications

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“…It has been described earlier that hydroxybupropion, the metabolite generated by CYP2B6, has the highest potency (Schroeder, 1983;Martin et al, 1990). Pharmacological administration of cortisone and prednisone, high endogenous cortisone during stress, or the use of 11b-HSD1 inhibitors (currently in development to treat metabolic syndrome and other diseases Anagnostis et al, 2013;Gathercole et al, 2013;Luo et al, 2013;Tiganescu et al, 2013;Venier et al, 2013) are likely to result in higher hydroxybupropion levels, which will necessitate a readjustment of the therapeutic dose of bupropion. Subjects receiving hormone replacement therapy, which leads to inhibition of CYP2B6, had diminished hydroxybupropion levels and increased erythro-and threohydrobupropion levels (Palovaara et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…In addition to the reduction of cortisone, 11b-HSD1 essentially converts the prodrug prednisone to its active form prednisolone (Hult et al, 1998), thereby enabling activation of the glucocorticoid receptor and regulating glucocorticoid-receptor-dependent target genes. Due to the adverse metabolic effects of prolonged periods of exposure to excessive glucocorticoid levels and the observed metabolic disturbances in transgenic mice overexpressing 11b-HSD1 in adipose tissue (Masuzaki and Flier, 2003), there are considerable efforts to develop inhibitors for the treatment of metabolic syndrome, with ongoing phase II trials (Hughes et al, 2008;Anagnostis et al, 2013;Gathercole et al, 2013;Venier et al, 2013). In addition, 11b-HSD1 inhibitors are currently under investigation for the treatment of several other diseases, including osteoporosis, glaucoma, age-associated impaired cognitive function, aging skin, and wound healing (Gathercole et al, 2013;Luo et al, 2013;Tiganescu et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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Formation of Threohydrobupropion from Bupropion Is Dependent on 11β-Hydroxysteroid Dehydrogenase 1

et al. 2013

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Bupropion is widely used for treatment of depression and as a smoking-cessation drug. Despite more than 20 years of therapeutic use, its metabolism is not fully understood. While CYP2B6 is known to form hydroxybupropion, the enzyme(s) generating erythro-and threohydrobupropion have long remained unclear. Previous experiments using microsomal preparations and the nonspecific inhibitor glycyrrhetinic acid suggested a role for 11b-hydroxysteroid dehydrogenase 1 (11b-HSD1) in the formation of both erythro-and threohydrobupropion. 11b-HSD1 catalyzes the conversion of inactive glucocorticoids (cortisone, prednisone) to their active forms (cortisol, prednisolone). Moreover, it accepts several other substrates. Here, we used for the first time recombinant 11b-HSD1 to assess its role in the carbonyl reduction of bupropion. Furthermore, we applied human, rat, and mouse liver microsomes and a selective inhibitor to characterize species-specific differences and to estimate the relative contribution of 11b-HSD1 to bupropion metabolism. The results revealed 11b-HSD1 as the major enzyme responsible for threohydrobupropion formation. The reaction was stereoselective and no erythrohydrobupropion was formed. Human liver microsomes showed 10 and 80 times higher activity than rat and mouse liver microsomes, respectively. The formation of erythrohydrobupropion was not altered in experiments with microsomes from 11b-HSD1-deficient mice or upon incubation with 11b-HSD1 inhibitor, indicating the existence of another carbonyl reductase that generates erythrohydrobupropion. Molecular docking supported the experimental findings and suggested that 11b-HSD1 selectively converts R-bupropion to threohydrobupropion. Enzyme inhibition experiments suggested that exposure to bupropion is not likely to impair 11b-HSD1-dependent glucocorticoid activation but that pharmacological administration of cortisone or prednisone may inhibit 11b-HSD1-dependent bupropion metabolism.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Formation of Threohydrobupropion from Bupropion Is Dependent on 11β-Hydroxysteroid Dehydrogenase 1

et al. 2013

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“…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 (IC 50 = 4 nM), mouse (IC 50 = 6 nM), and rat (IC 50 = 7 nM) 11β-HSD1 and exhibits only moderate inhibition of 11β-HSD2 (IC 50 = 4 μM). The compound was selective against hERG (IC 50 > 10 μM) and showed no CYP3A4 inhibition (IC 50 > 50 μM) or induction and no evidence of mutagenicity or teratogenicity in vitro.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

“…Optimization guided by X-ray structural information gave pyrrolidineurea 111 which allowed ex vivo mouse efficacy to be demonstrated in both fat and liver . 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 . Compound 112 is a potent inhibitor of human (IC 50 = 4 nM), mouse (IC 50 = 6 nM), and rat (IC 50 = 7 nM) 11β-HSD1 and exhibits only moderate inhibition of 11β-HSD2 (IC 50 = 4 μM).…”

Section: Medicinal Chemistry Of Inhibitors Of 11β-hsd1mentioning

confidence: 99%

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

2013

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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 11β-HSD1 inhibitors that have progressed into the clinic are summarized followed by a perspective from the authors.

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“…Thus, several adamantyl-containing 11β-HSD1 inhibitors exhibit high affinity and potency and some of them (e.g. AZD8329 and ABT-384) have reached clinical trials ( Figure 1) [26][27][28][29][30][31][32][33][34]. Although the evaluation of alternative polycyclic hydrocarbons may offer further opportunities for optimizing the space filling of the hydrophobic cavity, the use of other polycyclic substituents featuring different size or shape has only been briefly scrutinized (e.g.…”

Section: Design Synthesis and In Vitro Evaluation Of New Inhibitorsmentioning

confidence: 99%

Design, synthesis and in vivo study of novel pyrrolidine-based 11β-HSD1 inhibitors for age-related cognitive dysfunction

Leiva

Griñán-Ferré

Seira

et al. 2017

European Journal of Medicinal Chemistry

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Recent findings suggest that treatment with 11β-HSD1 inhibitors provides a novel approach to deal with age-related cognitive dysfunctions, including Alzheimer's disease. In this work we report potent 11β-HSD1 inhibitors featuring unexplored pyrrolidine-based polycyclic substituents. A selected candidate administered to 12-month-old SAMP8 mice for four weeks prevented memory deficits and displayed a neuroprotective action. This is the first time that 11β-HSD1 inhibitors have been studied in this broadly-used mouse model of accelerated senescence and late-onset Alzheimer's disease.

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Discovery of SAR184841, a potent and long-lasting inhibitor of 11β-hydroxysteroid dehydrogenase type 1, active in a physiopathological animal model of T2D

Cited by 11 publications

References 36 publications

Formation of Threohydrobupropion from Bupropion Is Dependent on 11β-Hydroxysteroid Dehydrogenase 1

Formation of Threohydrobupropion from Bupropion Is Dependent on 11β-Hydroxysteroid Dehydrogenase 1

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

Design, synthesis and in vivo study of novel pyrrolidine-based 11β-HSD1 inhibitors for age-related cognitive dysfunction

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