Discovery of 4-heteroarylbicyclo[2.2.2]octyltriazoles as potent and selective inhibitors of 11β-HSD1: Novel therapeutic agents for the treatment of metabolic syndrome

Xin Gu; Jasminka Dragovic; Gloria C. Koo; Sam L. Koprak; Cheryl Legrand; Steven S. Mundt; Kashmira Shah; Marty S. Springer; Eugene Y. Tan; Rolf Thieringer; Anne Hermanowski-Vosatka; Hratch J. Zokian; James M. Balkovec; Sherman T. Waddell

doi:10.1016/j.bmcl.2005.08.052

Discovery of 4-heteroarylbicyclo[2.2.2]octyltriazoles as potent and selective inhibitors of 11β-HSD1: Novel therapeutic agents for the treatment of metabolic syndrome

Xin Gu
, Jasminka Dragovic
, Gloria C. Koo
, Sam L. Koprak
, Cheryl Legrand
, Steven S. Mundt
, Kashmira Shah
, Marty S. Springer
, Eugene Y. Tan
, Rolf Thieringer
, Anne Hermanowski-Vosatka
, Hratch J. Zokian
, James M. Balkovec
, Sherman T. Waddell

Center for Discovery and Innovation

Merck

Research output: Contribution to journal › Article › peer-review

66 Scopus citations

Abstract

Replacement of the pentyl chain on our original bicyclo[2.2.2]octyltriazole leads 1 and 2 has led to the discovery that heteroaryl substituted bicyclo[2.2.2]octyltriazoles are potent and selective 11β-hydroxysteroid dehydrogenase type I (11β-HSD1) inhibitors with excellent pharmacokinetic profiles.

Original language	English
Pages (from-to)	5266-5269
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	15
Issue number	23
DOIs	https://doi.org/10.1016/j.bmcl.2005.08.052
State	Published - 1 Dec 2005

Keywords

11β-HSD1
11β-HSD2
11β-Hydroxysteroid dehydrogenase type I
Bicyclo[2.2.2]octyltriazole
Cortisol
Cortisone
Glucocorticoids
Heterocycle
Imidazole
Metabolic syndrome
Oxadiazole
Pharmacodynamic assay
Pharmacokinectics
Triazole

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10.1016/j.bmcl.2005.08.052

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Gu, X., Dragovic, J., Koo, G. C., Koprak, S. L., Legrand, C., Mundt, S. S., Shah, K., Springer, M. S., Tan, E. Y., Thieringer, R., Hermanowski-Vosatka, A., Zokian, H. J., Balkovec, J. M., & Waddell, S. T. (2005). Discovery of 4-heteroarylbicyclo[2.2.2]octyltriazoles as potent and selective inhibitors of 11β-HSD1: Novel therapeutic agents for the treatment of metabolic syndrome. Bioorganic and Medicinal Chemistry Letters, 15(23), 5266-5269. https://doi.org/10.1016/j.bmcl.2005.08.052

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title = "Discovery of 4-heteroarylbicyclo[2.2.2]octyltriazoles as potent and selective inhibitors of 11β-HSD1: Novel therapeutic agents for the treatment of metabolic syndrome",

abstract = "Replacement of the pentyl chain on our original bicyclo[2.2.2]octyltriazole leads 1 and 2 has led to the discovery that heteroaryl substituted bicyclo[2.2.2]octyltriazoles are potent and selective 11β-hydroxysteroid dehydrogenase type I (11β-HSD1) inhibitors with excellent pharmacokinetic profiles.",

keywords = "11β-HSD1, 11β-HSD2, 11β-Hydroxysteroid dehydrogenase type I, Bicyclo[2.2.2]octyltriazole, Cortisol, Cortisone, Glucocorticoids, Heterocycle, Imidazole, Metabolic syndrome, Oxadiazole, Pharmacodynamic assay, Pharmacokinectics, Triazole",

author = "Xin Gu and Jasminka Dragovic and Koo, \{Gloria C.\} and Koprak, \{Sam L.\} and Cheryl Legrand and Mundt, \{Steven S.\} and Kashmira Shah and Springer, \{Marty S.\} and Tan, \{Eugene Y.\} and Rolf Thieringer and Anne Hermanowski-Vosatka and Zokian, \{Hratch J.\} and Balkovec, \{James M.\} and Waddell, \{Sherman T.\}",

year = "2005",

month = dec,

day = "1",

doi = "10.1016/j.bmcl.2005.08.052",

language = "English",

volume = "15",

pages = "5266--5269",

journal = "Bioorganic and Medicinal Chemistry Letters",

issn = "0960-894X",

publisher = "Elsevier Ltd",

number = "23",

}

Gu, X, Dragovic, J, Koo, GC, Koprak, SL, Legrand, C, Mundt, SS, Shah, K, Springer, MS, Tan, EY, Thieringer, R, Hermanowski-Vosatka, A, Zokian, HJ, Balkovec, JM & Waddell, ST 2005, 'Discovery of 4-heteroarylbicyclo[2.2.2]octyltriazoles as potent and selective inhibitors of 11β-HSD1: Novel therapeutic agents for the treatment of metabolic syndrome', Bioorganic and Medicinal Chemistry Letters, vol. 15, no. 23, pp. 5266-5269. https://doi.org/10.1016/j.bmcl.2005.08.052

Discovery of 4-heteroarylbicyclo[2.2.2]octyltriazoles as potent and selective inhibitors of 11β-HSD1: Novel therapeutic agents for the treatment of metabolic syndrome. / Gu, Xin; Dragovic, Jasminka; Koo, Gloria C. et al.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 15, No. 23, 01.12.2005, p. 5266-5269.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Discovery of 4-heteroarylbicyclo[2.2.2]octyltriazoles as potent and selective inhibitors of 11β-HSD1

T2 - Novel therapeutic agents for the treatment of metabolic syndrome

AU - Gu, Xin

AU - Dragovic, Jasminka

AU - Koo, Gloria C.

AU - Koprak, Sam L.

AU - Legrand, Cheryl

AU - Mundt, Steven S.

AU - Shah, Kashmira

AU - Springer, Marty S.

AU - Tan, Eugene Y.

AU - Thieringer, Rolf

AU - Hermanowski-Vosatka, Anne

AU - Zokian, Hratch J.

AU - Balkovec, James M.

AU - Waddell, Sherman T.

PY - 2005/12/1

Y1 - 2005/12/1

N2 - Replacement of the pentyl chain on our original bicyclo[2.2.2]octyltriazole leads 1 and 2 has led to the discovery that heteroaryl substituted bicyclo[2.2.2]octyltriazoles are potent and selective 11β-hydroxysteroid dehydrogenase type I (11β-HSD1) inhibitors with excellent pharmacokinetic profiles.

AB - Replacement of the pentyl chain on our original bicyclo[2.2.2]octyltriazole leads 1 and 2 has led to the discovery that heteroaryl substituted bicyclo[2.2.2]octyltriazoles are potent and selective 11β-hydroxysteroid dehydrogenase type I (11β-HSD1) inhibitors with excellent pharmacokinetic profiles.

KW - 11β-HSD1

KW - 11β-HSD2

KW - 11β-Hydroxysteroid dehydrogenase type I

KW - Bicyclo[2.2.2]octyltriazole

KW - Cortisol

KW - Cortisone

KW - Glucocorticoids

KW - Heterocycle

KW - Imidazole

KW - Metabolic syndrome

KW - Oxadiazole

KW - Pharmacodynamic assay

KW - Pharmacokinectics

KW - Triazole

UR - https://www.scopus.com/pages/publications/26844460594

U2 - 10.1016/j.bmcl.2005.08.052

DO - 10.1016/j.bmcl.2005.08.052

M3 - Article

C2 - 16185866

AN - SCOPUS:26844460594

SN - 0960-894X

VL - 15

SP - 5266

EP - 5269

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 23

ER -

Discovery of 4-heteroarylbicyclo[2.2.2]octyltriazoles as potent and selective inhibitors of 11β-HSD1: Novel therapeutic agents for the treatment of metabolic syndrome

Abstract

Keywords

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