Discovery of 12-thiazole abietanes as selective inhibitors of the human metabolic serine hydrolase hABHD16A

Tiina J. Ahonen; Juha R. Savinainen; Jari Yli-Kauhaluoma; Eija Kalso; Jarmo T. Laitinen; Vânia M. Moreira

doi:10.1021/acsmedchemlett.8b00442

Discovery of 12-thiazole abietanes as selective inhibitors of the human metabolic serine hydrolase hABHD16A

Tiina J. Ahonen, Juha R. Savinainen, Jari Yli-Kauhaluoma, Eija Kalso, Jarmo T. Laitinen, Vânia M. Moreira

Strathclyde Institute Of Pharmacy And Biomedical Sciences

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Abstract

Screening of an in-house library of compounds identified 12-thiazole abietanes as a new class of reversible inhibitors of the human metabolic serine hydrolase. Further optimization of the first hit compound lead to the 2-methylthiazole derivative 18, with an IC₅₀ value of 3.4 ± 0.2 µM and promising selectivity. ABHD16A has been highlighted as a new target for in-flammation-mediated pain, although selective inhibitors of hABHD16A (human ABHD16A) have not yet been reported. Our study presents abietane-type diterpenoids as an attractive starting point for the design of selective ABHD16A inhibitors, which will contribute towards understanding the significance of hABHD16A inhibition in vivo.

Original language	English
Pages (from-to)	1269-1273
Number of pages	5
Journal	ACS Medicinal Chemistry Letters
Volume	9
Issue number	12
Early online date	13 Nov 2018
DOIs	https://doi.org/10.1021/acsmedchemlett.8b00442
Publication status	Published - 13 Nov 2018

Keywords

dehydroabietic acid
hABHD16A inhibitor
lysophosphatidylserine
metabolic serine hydrolase

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10.1021/acsmedchemlett.8b00442

Ahonen-etal-ACS-MCL-2018-Discovery-of-12-thiazole-abietanes-as-selective-inhibitorsAccepted author manuscript, 337 KB

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title = "Discovery of 12-thiazole abietanes as selective inhibitors of the human metabolic serine hydrolase hABHD16A",

abstract = "Screening of an in-house library of compounds identified 12-thiazole abietanes as a new class of reversible inhibitors of the human metabolic serine hydrolase. Further optimization of the first hit compound lead to the 2-methylthiazole derivative 18, with an IC50 value of 3.4 ± 0.2 µM and promising selectivity. ABHD16A has been highlighted as a new target for in-flammation-mediated pain, although selective inhibitors of hABHD16A (human ABHD16A) have not yet been reported. Our study presents abietane-type diterpenoids as an attractive starting point for the design of selective ABHD16A inhibitors, which will contribute towards understanding the significance of hABHD16A inhibition in vivo.",

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author = "Ahonen, {Tiina J.} and Savinainen, {Juha R.} and Jari Yli-Kauhaluoma and Eija Kalso and Laitinen, {Jarmo T.} and Moreira, {V{\^a}nia M.}",

note = "This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Medicinal Chemistry Letters, copyright {\textcopyright} American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acsmedchemlett.8b00442.",

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AU - Ahonen, Tiina J.

AU - Savinainen, Juha R.

AU - Yli-Kauhaluoma, Jari

AU - Kalso, Eija

AU - Laitinen, Jarmo T.

AU - Moreira, Vânia M.

N1 - This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Medicinal Chemistry Letters, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acsmedchemlett.8b00442.

PY - 2018/11/13

Y1 - 2018/11/13

N2 - Screening of an in-house library of compounds identified 12-thiazole abietanes as a new class of reversible inhibitors of the human metabolic serine hydrolase. Further optimization of the first hit compound lead to the 2-methylthiazole derivative 18, with an IC50 value of 3.4 ± 0.2 µM and promising selectivity. ABHD16A has been highlighted as a new target for in-flammation-mediated pain, although selective inhibitors of hABHD16A (human ABHD16A) have not yet been reported. Our study presents abietane-type diterpenoids as an attractive starting point for the design of selective ABHD16A inhibitors, which will contribute towards understanding the significance of hABHD16A inhibition in vivo.

AB - Screening of an in-house library of compounds identified 12-thiazole abietanes as a new class of reversible inhibitors of the human metabolic serine hydrolase. Further optimization of the first hit compound lead to the 2-methylthiazole derivative 18, with an IC50 value of 3.4 ± 0.2 µM and promising selectivity. ABHD16A has been highlighted as a new target for in-flammation-mediated pain, although selective inhibitors of hABHD16A (human ABHD16A) have not yet been reported. Our study presents abietane-type diterpenoids as an attractive starting point for the design of selective ABHD16A inhibitors, which will contribute towards understanding the significance of hABHD16A inhibition in vivo.

KW - dehydroabietic acid

KW - hABHD16A inhibitor

KW - lysophosphatidylserine

KW - metabolic serine hydrolase

UR - https://pubs.acs.org/journal/amclct

U2 - 10.1021/acsmedchemlett.8b00442

DO - 10.1021/acsmedchemlett.8b00442

M3 - Article

SN - 1948-5875

VL - 9

SP - 1269

EP - 1273

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

IS - 12

ER -

Discovery of 12-thiazole abietanes as selective inhibitors of the human metabolic serine hydrolase hABHD16A

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