Discovery of adamantyl heterocyclic ketones as potent 11 beta-hydroxysteroid dehydrogenase type 1 inhibitors

Xiangdong Su, Nigel Vicker, Mark P. Thomas, Fabienne Pradaux-Caggiano, Heather Halem, Michael D. Culler, Barry V. L. Potter

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

11 beta-Hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) plays a key role in converting intracellular cortisone to physiologically active cortisol, which is implicated in the development of several phenotypes of metabolic syndrome. Inhibition of 11 beta-HSD1 activity with selective inhibitors has beneficial effects on various conditions, including diabetes, dyslipidemia and obesity, and therefore constitutes a promising strategy to discover novel therapies for metabolic and cardiovascular diseases. A series of novel adamantyl heterocyclic ketones provides potent and selective inhibitors of human 11 beta-HSD1. Lead compounds display low nanomolar inhibition against human and mouse 11 beta-HSD1 and are selective with no activity against 11 beta-HSD2 and 17 beta-HSD1. Selected potent 11 beta-HSD1 inhibitors show moderate metabolic stability upon incubation with human liver microsomes and weak inhibition of human CYP450 enzymes.
Original languageEnglish
Pages (from-to)1439-1451
JournalChemMedChem
Volume6
Issue number8
DOIs
Publication statusPublished - 1 Aug 2011

Fingerprint

11-beta-Hydroxysteroid Dehydrogenase Type 1
Ketones
11-beta-Hydroxysteroid Dehydrogenase Type 2
Lead compounds
Cortisone
Metabolic Diseases
Liver Microsomes
Medical problems
Dyslipidemias
Liver
Hydrocortisone
Cardiovascular Diseases
Obesity
Phenotype
Enzymes

Cite this

Discovery of adamantyl heterocyclic ketones as potent 11 beta-hydroxysteroid dehydrogenase type 1 inhibitors. / Su, Xiangdong; Vicker, Nigel; Thomas, Mark P.; Pradaux-Caggiano, Fabienne; Halem, Heather; Culler, Michael D.; Potter, Barry V. L.

In: ChemMedChem, Vol. 6, No. 8, 01.08.2011, p. 1439-1451.

Research output: Contribution to journalArticle

Su, X, Vicker, N, Thomas, MP, Pradaux-Caggiano, F, Halem, H, Culler, MD & Potter, BVL 2011, 'Discovery of adamantyl heterocyclic ketones as potent 11 beta-hydroxysteroid dehydrogenase type 1 inhibitors', ChemMedChem, vol. 6, no. 8, pp. 1439-1451. https://doi.org/10.1002/cmdc.201100144
Su, Xiangdong ; Vicker, Nigel ; Thomas, Mark P. ; Pradaux-Caggiano, Fabienne ; Halem, Heather ; Culler, Michael D. ; Potter, Barry V. L. / Discovery of adamantyl heterocyclic ketones as potent 11 beta-hydroxysteroid dehydrogenase type 1 inhibitors. In: ChemMedChem. 2011 ; Vol. 6, No. 8. pp. 1439-1451.
@article{52a9ac6288d8424b861a59eff2007804,
title = "Discovery of adamantyl heterocyclic ketones as potent 11 beta-hydroxysteroid dehydrogenase type 1 inhibitors",
abstract = "11 beta-Hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) plays a key role in converting intracellular cortisone to physiologically active cortisol, which is implicated in the development of several phenotypes of metabolic syndrome. Inhibition of 11 beta-HSD1 activity with selective inhibitors has beneficial effects on various conditions, including diabetes, dyslipidemia and obesity, and therefore constitutes a promising strategy to discover novel therapies for metabolic and cardiovascular diseases. A series of novel adamantyl heterocyclic ketones provides potent and selective inhibitors of human 11 beta-HSD1. Lead compounds display low nanomolar inhibition against human and mouse 11 beta-HSD1 and are selective with no activity against 11 beta-HSD2 and 17 beta-HSD1. Selected potent 11 beta-HSD1 inhibitors show moderate metabolic stability upon incubation with human liver microsomes and weak inhibition of human CYP450 enzymes.",
author = "Xiangdong Su and Nigel Vicker and Thomas, {Mark P.} and Fabienne Pradaux-Caggiano and Heather Halem and Culler, {Michael D.} and Potter, {Barry V. L.}",
year = "2011",
month = "8",
day = "1",
doi = "10.1002/cmdc.201100144",
language = "English",
volume = "6",
pages = "1439--1451",
journal = "ChemMedChem",
issn = "1860-7179",
publisher = "John Wiley and Sons Inc.",
number = "8",

}

TY - JOUR

T1 - Discovery of adamantyl heterocyclic ketones as potent 11 beta-hydroxysteroid dehydrogenase type 1 inhibitors

AU - Su, Xiangdong

AU - Vicker, Nigel

AU - Thomas, Mark P.

AU - Pradaux-Caggiano, Fabienne

AU - Halem, Heather

AU - Culler, Michael D.

AU - Potter, Barry V. L.

PY - 2011/8/1

Y1 - 2011/8/1

N2 - 11 beta-Hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) plays a key role in converting intracellular cortisone to physiologically active cortisol, which is implicated in the development of several phenotypes of metabolic syndrome. Inhibition of 11 beta-HSD1 activity with selective inhibitors has beneficial effects on various conditions, including diabetes, dyslipidemia and obesity, and therefore constitutes a promising strategy to discover novel therapies for metabolic and cardiovascular diseases. A series of novel adamantyl heterocyclic ketones provides potent and selective inhibitors of human 11 beta-HSD1. Lead compounds display low nanomolar inhibition against human and mouse 11 beta-HSD1 and are selective with no activity against 11 beta-HSD2 and 17 beta-HSD1. Selected potent 11 beta-HSD1 inhibitors show moderate metabolic stability upon incubation with human liver microsomes and weak inhibition of human CYP450 enzymes.

AB - 11 beta-Hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) plays a key role in converting intracellular cortisone to physiologically active cortisol, which is implicated in the development of several phenotypes of metabolic syndrome. Inhibition of 11 beta-HSD1 activity with selective inhibitors has beneficial effects on various conditions, including diabetes, dyslipidemia and obesity, and therefore constitutes a promising strategy to discover novel therapies for metabolic and cardiovascular diseases. A series of novel adamantyl heterocyclic ketones provides potent and selective inhibitors of human 11 beta-HSD1. Lead compounds display low nanomolar inhibition against human and mouse 11 beta-HSD1 and are selective with no activity against 11 beta-HSD2 and 17 beta-HSD1. Selected potent 11 beta-HSD1 inhibitors show moderate metabolic stability upon incubation with human liver microsomes and weak inhibition of human CYP450 enzymes.

UR - http://www.scopus.com/inward/record.url?scp=79960688526&partnerID=8YFLogxK

UR - http://dx.doi.org/10.1002/cmdc.201100144

U2 - 10.1002/cmdc.201100144

DO - 10.1002/cmdc.201100144

M3 - Article

VL - 6

SP - 1439

EP - 1451

JO - ChemMedChem

JF - ChemMedChem

SN - 1860-7179

IS - 8

ER -