Adamantyl carboxamides and acetamides as potent human 11β-hydroxysteroid dehydrogenase type 1 inhibitors

Su, Xiaoyan; Halem, Heather; Thomas, Mark; Moutrille, Cecille; Culler, Michael D.; Vicker, Nigel; Potter, Barry V. L.

doi:10.1016/j.bmc.2012.08.056

Cited by 11 publications

(10 citation statements)

References 33 publications

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“…In order to improve selectivity, potency and pharmacokinetic parameters of initially discovered 11β-HSD1 inhibitors, several groups implemented scaffold hopping and structure-activity relationship (SAR) studies on the basis of docking studies [100–105]. Following chemical synthesis the same approach is often also used for binding mode explanations [106–108].…”

Section: Examples From the Sdr Familymentioning

confidence: 99%

Virtual screening applications in short-chain dehydrogenase/reductase research

Beck

Kaserer

Schuster

et al. 2017

The Journal of Steroid Biochemistry and Molecular Biology

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Several members of the short-chain dehydrogenase/reductase (SDR) enzyme family play fundamental roles in adrenal and gonadal steroidogenesis as well as in the metabolism of steroids, oxysterols, bile acids, and retinoids in peripheral tissues, thereby controlling the local activation of their cognate receptors. Some of these SDRs are considered as promising therapeutic targets, for example to treat estrogen-/androgen-dependent and corticosteroid-related diseases, whereas others are considered as anti-targets as their inhibition may lead to disturbances of endocrine functions, thereby contributing to the development and progression of diseases. Nevertheless, the physiological functions of about half of all SDR members are still unknown. In this respect, in silico tools are highly valuable in drug discovery for lead molecule identification, in toxicology screenings to facilitate the identification of hazardous chemicals, and in fundamental research for substrate identification and enzyme characterization. Regarding SDRs, computational methods have been employed for a variety of applications including drug discovery, enzyme characterization and substrate identification, as well as identification of potential endocrine disrupting chemicals (EDC). This review provides an overview of the efforts undertaken in the field of virtual screening supported identification of bioactive molecules in SDR research. In addition, it presents an outlook and addresses the opportunities and limitations of computational modeling and in vitro validation methods.

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Section: Examples From the Sdr Familymentioning

confidence: 99%

Virtual screening applications in short-chain dehydrogenase/reductase research

Beck

Kaserer

Schuster

et al. 2017

The Journal of Steroid Biochemistry and Molecular Biology

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“…The thiadiazole derivatives with an ethanone sulphide linker (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18) were generated by a nucleophilic coupling reaction between the corresponding aryl bromomethyl ketone and 5-methyl-1,3,4-thiadiazole-2-thiol under basic conditions. The sulphoxide and sulphone derivatives (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) were prepared by oxidation of the corresponding sulphides with m-CPBA. Similarly, compounds 31-34 were also prepared from the corresponding 5-substituted 1,3,4-thiadiazole-2-thiol via a nucleophilic substitution reaction (Scheme 1).…”

Section: Chemistrymentioning

confidence: 99%

“…A colourless oil (38 mg, 30%) was obtained. 1-(4-Methoxyphenyl)-2-((5-methyl-1,3,4-thiadiazol-2-yl)sulfonyl)ethanone (22). A colourless oil (80 mg, 59%) was obtained.…”

Section: General Procedures B: Synthesis Of Aryl Ethanone Sulphoxide ...mentioning

confidence: 99%

“…20 Our previous efforts to identify a suitable surrogate for the metabolically labile adamantyl group in the adamantyl carboxamide 11b-HSD1 inhibitor series led to the discovery of some new templates with potential for further modification. 22 In efforts to improve the pharmacokinetic properties of these adamantyl ethanone thiadiazole derivatives, we have synthesized and evaluated compounds with a substituted phenyl group as a replacement for the hydrophobic adamantyl moiety. Here we report the synthesis and the structure-activity relationship of a range of phenyl ethanone thiadiazole compounds as novel, potent and selective inhibitors of human 11b-HSD1.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and evaluation of thiadiazole derivatives as inhibitors of 11β-hydroxysteroid dehydrogenase type 1

Pradaux-Caggiano

Vicker

et al. 2012

Med. Chem. Commun.

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Regulation of tissue-specific glucocorticoid action by inhibiting 11b-HSD1 activity is regarded as a potential viable treatment for metabolic and cardiovascular diseases. Our effort to find an alternative to the highly favoured adamantyl moiety found in many potent 11b-HSD1 inhibitors led to the synthesis and SAR study of a series of phenyl ethanone thiadiazole derivatives. Potent compounds were identified with IC 50 values in the range 100-300 nM in biological evaluation on an HEK293 cell line stably transfected with the human HSD11B1 gene. These compounds are selective with no activity against human 11b-HSD2. An SAR study revealed the favoured combination of phenyl substitution and the linker system being meta-methoxy with a sulphide linker (18) or a para-trifluoromethyl with sulphoxide linker (27). Docking of 3 into a crystal structure of the enzyme shows how the substituted phenyl group of this new series might mimic the adamantane motif. Potent inhibitors 18 and 27 are new templates for further optimization.

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“…Selective inhibitors of 11 -HSD2 are expected to benefit a variety of metabolic disorders, including insulin resistance, dyslipidemia, and obesity. 2-Amino-N-(adamant-2-yl) acetamide was found to act, in a mouse model, as a potent and selective 11--hydroxysteroid dehydrogenase (HSD) inhibitor [6]. The compound lowered body weight, insulin levels, fasting glucose levels, triglycerides, and cholesterol in diet-induced obese mice.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Docking Studies of the NovelN-(2,2-Di(1H-pyrrol-2-yl)ethyl)adamantane-1-carboxamide, a Potential 11β-HSD1 Inhibitor

Gallardo-Alfonzo

Ocampo-Néstor

Contreras-Celedón

et al. 2014

Journal of Chemistry

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Adamantyl carboxamides and acetamides as potent human 11β-hydroxysteroid dehydrogenase type 1 inhibitors

Abstract: Graphical abstractSeries of adamantyl carboxamide and acetamide derivatives were identified, providing potent and selective inhibitors of the therapeutic target human 11β-hydroxysteroid dehydrogenase type 1.

Cited by 11 publications

References 33 publications

Virtual screening applications in short-chain dehydrogenase/reductase research

Virtual screening applications in short-chain dehydrogenase/reductase research

Synthesis and evaluation of thiadiazole derivatives as inhibitors of 11β-hydroxysteroid dehydrogenase type 1

Synthesis and Docking Studies of the NovelN-(2,2-Di(1H-pyrrol-2-yl)ethyl)adamantane-1-carboxamide, a Potential 11β-HSD1 Inhibitor

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