Discovery of a Potent Thiazolidine Free Fatty Acid Receptor 2 Agonist with Favorable Pharmacokinetic Properties

Anders Højgaard Hansen; Eugenia Sergeev; Daniele Bolognini; Richard R. Sprenger; Jeppe Hvidtfeldt Ekberg; Christer S. Ejsing; Christine J. McKenzie; Elisabeth Rexen Ulven; Graeme Milligan; Trond Ulven

doi:10.1021/acs.jmedchem.8b00855

Discovery of a Potent Thiazolidine Free Fatty Acid Receptor 2 Agonist with Favorable Pharmacokinetic Properties

Anders Højgaard Hansen, Eugenia Sergeev, Daniele Bolognini, Richard R. Sprenger, Jeppe Hvidtfeldt Ekberg, Christer S. Ejsing, Christine J. McKenzie, Elisabeth Rexen Ulven, Graeme Milligan, Trond Ulven^*

^*Corresponding author for this work

11 Citations (Scopus)

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Abstract

Free fatty acid receptor 2 (FFA2/GPR43) is a receptor for short-chain fatty acids reported to be involved in regulation of metabolism, appetite, fat accumulation, and inflammatory responses and is a potential target for treatment of various inflammatory and metabolic diseases. By bioisosteric replacement of the central pyrrolidine core of a previously disclosed FFA2 agonist with a synthetically more tractable thiazolidine, we were able to rapidly synthesize and screen analogues modified at both the 2- and 3-positions on the thiazolidine core. Herein, we report SAR exploration of thiazolidine FFA2 agonists and the identification of 31 (TUG-1375), a compound with significantly increased potency (7-fold in a cAMP assay) and reduced lipophilicity (50-fold reduced clogP) relative to the pyrrolidine lead structure. The compound has high solubility, high chemical, microsomal, and hepatocyte stability, and favorable pharmacokinetic properties and was confirmed to induce human neutrophil mobilization and to inhibit lipolysis in murine adipocytes.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	61
Issue number	21
Pages (from-to)	9534-9550
Number of pages	17
ISSN	0022-2623
DOIs	https://doi.org/10.1021/acs.jmedchem.8b00855
Publication status	Published - 2018

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Discovery of a Potent Thiazolidine Free Fatty Acid Receptor 2 Agonist with Favorable Pharmacokinetic PropertiesFinal published version, 4.19 MBLicence: CC BY

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title = "Discovery of a Potent Thiazolidine Free Fatty Acid Receptor 2 Agonist with Favorable Pharmacokinetic Properties",

abstract = "Free fatty acid receptor 2 (FFA2/GPR43) is a receptor for short-chain fatty acids reported to be involved in regulation of metabolism, appetite, fat accumulation, and inflammatory responses and is a potential target for treatment of various inflammatory and metabolic diseases. By bioisosteric replacement of the central pyrrolidine core of a previously disclosed FFA2 agonist with a synthetically more tractable thiazolidine, we were able to rapidly synthesize and screen analogues modified at both the 2- and 3-positions on the thiazolidine core. Herein, we report SAR exploration of thiazolidine FFA2 agonists and the identification of 31 (TUG-1375), a compound with significantly increased potency (7-fold in a cAMP assay) and reduced lipophilicity (50-fold reduced clogP) relative to the pyrrolidine lead structure. The compound has high solubility, high chemical, microsomal, and hepatocyte stability, and favorable pharmacokinetic properties and was confirmed to induce human neutrophil mobilization and to inhibit lipolysis in murine adipocytes.",

author = "Hansen, {Anders H{\o}jgaard} and Eugenia Sergeev and Daniele Bolognini and Sprenger, {Richard R.} and Ekberg, {Jeppe Hvidtfeldt} and Ejsing, {Christer S.} and McKenzie, {Christine J.} and {Rexen Ulven}, Elisabeth and Graeme Milligan and Trond Ulven",

year = "2018",

doi = "10.1021/acs.jmedchem.8b00855",

language = "English",

volume = "61",

pages = "9534--9550",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

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TY - JOUR

T1 - Discovery of a Potent Thiazolidine Free Fatty Acid Receptor 2 Agonist with Favorable Pharmacokinetic Properties

AU - Hansen, Anders Højgaard

AU - Sergeev, Eugenia

AU - Bolognini, Daniele

AU - Sprenger, Richard R.

AU - Ekberg, Jeppe Hvidtfeldt

AU - Ejsing, Christer S.

AU - McKenzie, Christine J.

AU - Rexen Ulven, Elisabeth

AU - Milligan, Graeme

AU - Ulven, Trond

PY - 2018

Y1 - 2018

N2 - Free fatty acid receptor 2 (FFA2/GPR43) is a receptor for short-chain fatty acids reported to be involved in regulation of metabolism, appetite, fat accumulation, and inflammatory responses and is a potential target for treatment of various inflammatory and metabolic diseases. By bioisosteric replacement of the central pyrrolidine core of a previously disclosed FFA2 agonist with a synthetically more tractable thiazolidine, we were able to rapidly synthesize and screen analogues modified at both the 2- and 3-positions on the thiazolidine core. Herein, we report SAR exploration of thiazolidine FFA2 agonists and the identification of 31 (TUG-1375), a compound with significantly increased potency (7-fold in a cAMP assay) and reduced lipophilicity (50-fold reduced clogP) relative to the pyrrolidine lead structure. The compound has high solubility, high chemical, microsomal, and hepatocyte stability, and favorable pharmacokinetic properties and was confirmed to induce human neutrophil mobilization and to inhibit lipolysis in murine adipocytes.

AB - Free fatty acid receptor 2 (FFA2/GPR43) is a receptor for short-chain fatty acids reported to be involved in regulation of metabolism, appetite, fat accumulation, and inflammatory responses and is a potential target for treatment of various inflammatory and metabolic diseases. By bioisosteric replacement of the central pyrrolidine core of a previously disclosed FFA2 agonist with a synthetically more tractable thiazolidine, we were able to rapidly synthesize and screen analogues modified at both the 2- and 3-positions on the thiazolidine core. Herein, we report SAR exploration of thiazolidine FFA2 agonists and the identification of 31 (TUG-1375), a compound with significantly increased potency (7-fold in a cAMP assay) and reduced lipophilicity (50-fold reduced clogP) relative to the pyrrolidine lead structure. The compound has high solubility, high chemical, microsomal, and hepatocyte stability, and favorable pharmacokinetic properties and was confirmed to induce human neutrophil mobilization and to inhibit lipolysis in murine adipocytes.

U2 - 10.1021/acs.jmedchem.8b00855

DO - 10.1021/acs.jmedchem.8b00855

M3 - Journal article

C2 - 30247908

AN - SCOPUS:85054969142

SN - 0022-2623

VL - 61

SP - 9534

EP - 9550

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 21

ER -

Discovery of a Potent Thiazolidine Free Fatty Acid Receptor 2 Agonist with Favorable Pharmacokinetic Properties

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