Bicyclo[2.2.2]octyltriazole inhibitors of 11β-hydoxysteroid dehydrogenase type 1. Pharmacological agents for the treatment of metabolic syndrome

Milana Maletic; Aaron Leeman; Michael Szymonifka; Steven S. Mundt; Hratch J. Zokian; Kashmira Shah; Jasminka Dragovic; Kathy Lyons; Rolf Thieringer; Anne H. Vosatka; James Balkovec; Sherman T. Waddell

doi:10.1016/j.bmcl.2011.01.018

Bicyclo[2.2.2]octyltriazole inhibitors of 11β-hydoxysteroid dehydrogenase type 1. Pharmacological agents for the treatment of metabolic syndrome

Milana Maletic
, Aaron Leeman
, Michael Szymonifka
, Steven S. Mundt
, Hratch J. Zokian
, Kashmira Shah
, Jasminka Dragovic
, Kathy Lyons
, Rolf Thieringer
, Anne H. Vosatka
, James Balkovec
, Sherman T. Waddell

Center for Discovery and Innovation

Merck

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

15 Scopus citations

Abstract

Following the discovery of a metabolic 'soft-spot' on a bicyclo[2.2.2]octyltriazole lead, an extensive effort was undertaken to block the oxidative metabolism and improve PK of this potent HSD1 lead. In this communication, SAR survey focusing on various alkyl chain replacements will be detailed. This effort culminated in the discovery of a potent ethyl sulfone inhibitor with an improved PK profile across species and improved physical properties.

Original language	English
Pages (from-to)	2568-2572
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	21
Issue number	8
DOIs	https://doi.org/10.1016/j.bmcl.2011.01.018
State	Published - 15 Apr 2011

Keywords

11β-HSD1 inhibitor
Metabolic Syndrome
Sulfone

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10.1016/j.bmcl.2011.01.018

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Maletic, M., Leeman, A., Szymonifka, M., Mundt, S. S., Zokian, H. J., Shah, K., Dragovic, J., Lyons, K., Thieringer, R., Vosatka, A. H., Balkovec, J., & Waddell, S. T. (2011). Bicyclo[2.2.2]octyltriazole inhibitors of 11β-hydoxysteroid dehydrogenase type 1. Pharmacological agents for the treatment of metabolic syndrome. Bioorganic and Medicinal Chemistry Letters, 21(8), 2568-2572. https://doi.org/10.1016/j.bmcl.2011.01.018

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title = "Bicyclo[2.2.2]octyltriazole inhibitors of 11β-hydoxysteroid dehydrogenase type 1. Pharmacological agents for the treatment of metabolic syndrome",

abstract = "Following the discovery of a metabolic 'soft-spot' on a bicyclo[2.2.2]octyltriazole lead, an extensive effort was undertaken to block the oxidative metabolism and improve PK of this potent HSD1 lead. In this communication, SAR survey focusing on various alkyl chain replacements will be detailed. This effort culminated in the discovery of a potent ethyl sulfone inhibitor with an improved PK profile across species and improved physical properties.",

keywords = "11β-HSD1 inhibitor, Metabolic Syndrome, Sulfone",

author = "Milana Maletic and Aaron Leeman and Michael Szymonifka and Mundt, \{Steven S.\} and Zokian, \{Hratch J.\} and Kashmira Shah and Jasminka Dragovic and Kathy Lyons and Rolf Thieringer and Vosatka, \{Anne H.\} and James Balkovec and Waddell, \{Sherman T.\}",

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Maletic, M, Leeman, A, Szymonifka, M, Mundt, SS, Zokian, HJ, Shah, K, Dragovic, J, Lyons, K, Thieringer, R, Vosatka, AH, Balkovec, J & Waddell, ST 2011, 'Bicyclo[2.2.2]octyltriazole inhibitors of 11β-hydoxysteroid dehydrogenase type 1. Pharmacological agents for the treatment of metabolic syndrome', Bioorganic and Medicinal Chemistry Letters, vol. 21, no. 8, pp. 2568-2572. https://doi.org/10.1016/j.bmcl.2011.01.018

TY - JOUR

T1 - Bicyclo[2.2.2]octyltriazole inhibitors of 11β-hydoxysteroid dehydrogenase type 1. Pharmacological agents for the treatment of metabolic syndrome

AU - Maletic, Milana

AU - Leeman, Aaron

AU - Szymonifka, Michael

AU - Mundt, Steven S.

AU - Zokian, Hratch J.

AU - Shah, Kashmira

AU - Dragovic, Jasminka

AU - Lyons, Kathy

AU - Thieringer, Rolf

AU - Vosatka, Anne H.

AU - Balkovec, James

AU - Waddell, Sherman T.

PY - 2011/4/15

Y1 - 2011/4/15

N2 - Following the discovery of a metabolic 'soft-spot' on a bicyclo[2.2.2]octyltriazole lead, an extensive effort was undertaken to block the oxidative metabolism and improve PK of this potent HSD1 lead. In this communication, SAR survey focusing on various alkyl chain replacements will be detailed. This effort culminated in the discovery of a potent ethyl sulfone inhibitor with an improved PK profile across species and improved physical properties.

AB - Following the discovery of a metabolic 'soft-spot' on a bicyclo[2.2.2]octyltriazole lead, an extensive effort was undertaken to block the oxidative metabolism and improve PK of this potent HSD1 lead. In this communication, SAR survey focusing on various alkyl chain replacements will be detailed. This effort culminated in the discovery of a potent ethyl sulfone inhibitor with an improved PK profile across species and improved physical properties.

KW - 11β-HSD1 inhibitor

KW - Metabolic Syndrome

KW - Sulfone

UR - https://www.scopus.com/pages/publications/79953283569

U2 - 10.1016/j.bmcl.2011.01.018

DO - 10.1016/j.bmcl.2011.01.018

M3 - Article

C2 - 21421311

AN - SCOPUS:79953283569

SN - 0960-894X

VL - 21

SP - 2568

EP - 2572

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 8

ER -

Bicyclo[2.2.2]octyltriazole inhibitors of 11β-hydoxysteroid dehydrogenase type 1. Pharmacological agents for the treatment of metabolic syndrome

Abstract

Keywords

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