Optimisation of biphenyl acetic acid inhibitors of diacylglycerol acetyl transferase 1-the discovery of AZD2353

Michael J. Waring; Alan M. Birch; Susan Birtles; Linda K. Buckett; Roger J. Butlin; Leonie Campbell; Pablo Morentin Gutierrez; Paul D. Kemmitt; Andrew G. Leach; Philip A. MacFaul; Charles O'Donnell; Andrew V. Turnbull

doi:10.1039/c2md20190a

Optimisation of biphenyl acetic acid inhibitors of diacylglycerol acetyl transferase 1-the discovery of AZD2353

Michael J. Waring, Alan M. Birch, Susan Birtles, Linda K. Buckett, Roger J. Butlin, Leonie Campbell, Pablo Morentin Gutierrez, Paul D. Kemmitt, Andrew G. Leach, Philip A. MacFaul, Charles O'Donnell, Andrew V. Turnbull

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

Abstract

Inhibition of diacylglycerol acetyl transferase 1 is of great interest in the treatment of diabetes, obesity and other diseases that constitute the metabolic syndrome. Small molecule inhibitors of the enzyme are often dogged with physicochemical property-related problems such as poor solubility. Herein, the optimisation of a series of biphenyl acetic acid inhibitors is reported. Focus on ligand efficiency and ligand lipophilicity efficiency and a strategy based on conformational restriction led to compounds with excellent potency and ADMET properties, culminating in the discovery of AZD2353.

Original language	English
Pages (from-to)	159-164
Number of pages	6
Journal	MedChemComm
Volume	4
Issue number	1
DOIs	https://doi.org/10.1039/c2md20190a
Publication status	Published - Jan 2013

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1039/c2md20190a

Cite this

@article{fd2cb67031f9495380600c2fb199e450,

title = "Optimisation of biphenyl acetic acid inhibitors of diacylglycerol acetyl transferase 1-the discovery of AZD2353",

abstract = "Inhibition of diacylglycerol acetyl transferase 1 is of great interest in the treatment of diabetes, obesity and other diseases that constitute the metabolic syndrome. Small molecule inhibitors of the enzyme are often dogged with physicochemical property-related problems such as poor solubility. Herein, the optimisation of a series of biphenyl acetic acid inhibitors is reported. Focus on ligand efficiency and ligand lipophilicity efficiency and a strategy based on conformational restriction led to compounds with excellent potency and ADMET properties, culminating in the discovery of AZD2353.",

author = "Waring, {Michael J.} and Birch, {Alan M.} and Susan Birtles and Buckett, {Linda K.} and Butlin, {Roger J.} and Leonie Campbell and Gutierrez, {Pablo Morentin} and Kemmitt, {Paul D.} and Leach, {Andrew G.} and MacFaul, {Philip A.} and Charles O'Donnell and Turnbull, {Andrew V.}",

year = "2013",

month = jan,

doi = "10.1039/c2md20190a",

language = "English",

volume = "4",

pages = "159--164",

journal = "MedChemComm",

issn = "2040-2503",

publisher = "Royal Society of Chemistry",

number = "1",

}

TY - JOUR

T1 - Optimisation of biphenyl acetic acid inhibitors of diacylglycerol acetyl transferase 1-the discovery of AZD2353

AU - Waring, Michael J.

AU - Birch, Alan M.

AU - Birtles, Susan

AU - Buckett, Linda K.

AU - Butlin, Roger J.

AU - Campbell, Leonie

AU - Gutierrez, Pablo Morentin

AU - Kemmitt, Paul D.

AU - Leach, Andrew G.

AU - MacFaul, Philip A.

AU - O'Donnell, Charles

AU - Turnbull, Andrew V.

PY - 2013/1

Y1 - 2013/1

N2 - Inhibition of diacylglycerol acetyl transferase 1 is of great interest in the treatment of diabetes, obesity and other diseases that constitute the metabolic syndrome. Small molecule inhibitors of the enzyme are often dogged with physicochemical property-related problems such as poor solubility. Herein, the optimisation of a series of biphenyl acetic acid inhibitors is reported. Focus on ligand efficiency and ligand lipophilicity efficiency and a strategy based on conformational restriction led to compounds with excellent potency and ADMET properties, culminating in the discovery of AZD2353.

AB - Inhibition of diacylglycerol acetyl transferase 1 is of great interest in the treatment of diabetes, obesity and other diseases that constitute the metabolic syndrome. Small molecule inhibitors of the enzyme are often dogged with physicochemical property-related problems such as poor solubility. Herein, the optimisation of a series of biphenyl acetic acid inhibitors is reported. Focus on ligand efficiency and ligand lipophilicity efficiency and a strategy based on conformational restriction led to compounds with excellent potency and ADMET properties, culminating in the discovery of AZD2353.

U2 - 10.1039/c2md20190a

DO - 10.1039/c2md20190a

M3 - Article

SN - 2040-2503

VL - 4

SP - 159

EP - 164

JO - MedChemComm

JF - MedChemComm

IS - 1

ER -

Optimisation of biphenyl acetic acid inhibitors of diacylglycerol acetyl transferase 1-the discovery of AZD2353

Abstract

UN SDGs

Access to Document

Fingerprint

Cite this