Discovery and biological evaluation of adamantyl amide 11β-HSD1 inhibitors

https://doi.org/10.1016/j.bmcl.2007.02.057Get rights and content

Abstract

A series of adamantyl amide 11β-HSD1 inhibitors has been discovered and chemically modified. Selected compounds are selective for 11β-HSD1 over 11β-HSD2 and possess excellent cellular potency in human and murine 11β-HSD1 assays. Good pharmacodynamic characteristics are observed in ex vivo assays.

Graphical abstract

The synthesis and biological activity of a series of adamantyl amide 11β-HSD1 inhibitors represented by 5 is reported.

  1. Download : Download full-size image

Section snippets

Acknowledgments

We thank Enamine Ltd for the provision of synthetic chemistry services and the Wellcome Trust for funding.

References and notes (14)

  • N.M. Morton et al.

    J. Biol. Chem.

    (2001)
  • A. Hermanowski-Vosatka et al.

    J. Exp. Med.

    (2005)
  • T. Cheeseright et al.

    J. Chem. Inf. Model

    (2006)
    T. Cheeseright et al.

    Expert. Opin. Drug. Discov.

    (2007)
  • R. Raag et al.

    Biochemistry

    (1991)
  • G. Arnaldi et al.

    J. Clin. Endocrinol. Metab.

    (2005)
  • J.R. Seckl et al.

    Endocrinology

    (2001)
  • Y. Kotelevtsev et al.

    Proc. Natl. Acad. Sci. U.S.A.

    (1997)
There are more references available in the full text version of this article.

Cited by (48)

  • Thiazolo[3,2-a]pyrimidin-5-one derivatives as a novel class of 11β-hydroxysteroid dehydrogenase inhibitors

    2018, Bioorganic Chemistry
    Citation Excerpt :

    The predicted positions of the ligands docked into 11β-HSD1 were characterized by a simultaneous lowering of the scoring function value, Docking Score [kJ/mol]; this corresponds to the high values of the ligand binding energy. In order to search for effective and selective inhibitors of 11β-HSD1, attention was paid to thiazole derivatives i.a. BVT-14225, BVT-2733, BVT-3498 [3,18], 2-amino-1,3-thiazol-4(5H)one [5,19,20], (1,3-benzothiazol-2-yl)benzenesulfonamides [21] and adamantyl amides [1]. The possibility of using thiazolo[3,2-a]pyrimidine-5-one derivatives as inhibitors of 11β-HSD1 have not been earlier studied and reported in the literature.

  • Synthesis of 2-{2-[(α/β-naphthalen-1-ylsulfonyl)amino]-1,3- thiazol-4-yl} acetamides with 11β-hydroxysteroid dehydrogenase inhibition and in combo antidiabetic activities

    2014, European Journal of Medicinal Chemistry
    Citation Excerpt :

    Several lines of evidence have implicated glucocorticoids and 11β-HSD1 activity in the etiology and/or maintenance of type 2 diabetes mellitus and metabolic syndrome. Consequently, it is thought that selective inhibition of 11β-HSD1 may provide a means of treating diabetes and other aspects of the metabolic syndrome, such as obesity [6]. Current studies suggest that inhibition of 11β-HSD1 increases hepatic insulin sensitivity along with decreased glucose production [2].

  • 11b-Hydroxysteroid dehydrogenase type 1 contributes to the balance between 7-keto- and 7-hydroxy-oxysterols in vivo

    2013, Biochemical Pharmacology
    Citation Excerpt :

    Inter-conversion of substrates and products was quantified under conditions of first order kinetics. Three forms of murine enzyme (n = 6/group) were used: (1) a truncated form of recombinant m11βHSD1 protein (N23Δ, gift from Dr Webster), (2) enzyme contained within murine hepatic microsomes and (3) a full-length m11βHSD1 protein expressed in stably transfected HEK293 cells [24]. Recombinant (14–28 μg/mL) or murine hepatic microsomal (240–260 μg/mL [19]) protein was incubated (30 min, 37 °C) with 7-oxysterols (0.02–20 μM) in potassium phosphate buffer (0.1 M, 0.1 mM EDTA, 20 mM cysteamine hydrochloride, pH 7.4), or with steroids (0.02–20 μM) in Krebs-Ringer buffer (containing 5 mM glucose), and the relevant cofactor (2 mM) for oxidation (NADP+ or NAD+) or reduction (NADPH or NADH).

View all citing articles on Scopus
View full text