Discovery of TUG-770: A Highly Potent Free Fatty Acid
Receptor 1 (FFA1/GPR40) Agonist for Treatment of Type 2 Diabetes

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Abstract

Free fatty acid receptor 1 (FFA1 or GPR40) enhances glucose-stimulated insulin secretion from pancreatic β-cells and currently attracts high interest as a new target for the treatment of type 2 diabetes. We here report the discovery of a highly potent FFA1 agonist with favorable physicochemical and pharmacokinetic properties. The compound efficiently normalizes glucose tolerance in diet-induced obese mice, an effect that is fully sustained after 29 days of chronic dosing.

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Ligand efficiency: a useful metric for lead selection.

Andrew Hopkins, Colin Groom, Alexander Alex (2004)

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TAK-875 versus placebo or glimepiride in type 2 diabetes mellitus: a phase 2, randomised, double-blind, placebo-controlled trial.

Charles F Burant, Prabhakar Viswanathan, John Marcinak … (2012)

Activation of free fatty acid receptor 1 (FFAR1; also known as G-protein-coupled receptor 40) by fatty acids stimulated glucose-dependent β-cell insulin secretion in preclinical models. We aimed to assess whether selective pharmacological activation of this receptor by TAK-875 in patients with type 2 diabetes mellitus improved glycaemic control without hypoglycaemia risk. We undertook a phase 2, randomised, double-blind, and placebo-controlled and active-comparator-controlled trial in outpatients with type 2 diabetes who had not responded to diet or metformin treatment. Patients were randomly assigned equally to receive placebo, TAK-875 (6·25, 25, 50, 100, or 200 mg), or glimepiride (4 mg) once daily for 12 weeks. Patients and investigators were masked to treatment assignment. The primary outcome was change in haemoglobin A(1c) (HbA(1c)) from baseline. Analysis included all patients randomly assigned to treatment groups who received at least one dose of double-blind study drug. The trial is registered at ClinicalTrials.gov, NCT01007097. 426 patients were randomly assigned to TAK-875 (n=303), placebo (n=61), and glimepiride (n=62). At week 12, significant least-squares mean reductions in HbA(1c) from baseline occurred in all TAK-875 (ranging from -1·12% [SE 0·113] with 50 mg to -0·65% [0·114] with 6·25 mg) and glimepiride (-1·05% [SE 0·111]) groups versus placebo (-0·13% [SE 0·115]; p value range 0·001 to <0·0001). Treatment-emergent hypoglycaemic events were similar in the TAK-875 and placebo groups (2% [n=7, all TAK-875 groups] vs 3% [n=2]); significantly higher rates were reported in the glimepiride group (19% [n=12]; p value range 0·010-0·002 vs all TAK-875 groups). Incidence of treatment-emergent adverse events was similar in the TAK-875 overall (49%; n=147, all TAK-875 groups) and placebo groups (48%, n=29) and was lower than in the glimepiride group (61%, n=38). TAK-875 significantly improved glycaemic control in patients with type 2 diabetes with minimum risk of hypoglycaemia. The results show that activation of FFAR1 is a viable therapeutic target for treatment of type 2 diabetes. Takeda Global Research and Development. Copyright © 2012 Elsevier Ltd. All rights reserved.

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Discovery of a potent and selective GPR120 agonist.

Graeme Milligan, Christine Kiel Hovgaard, Bharat Shimpukade … (2012)

GPR120 is a receptor of unsaturated long-chain fatty acids reported to mediate GLP-1 secretion, insulin sensitization, anti-inflammatory, and anti-obesity effects and is therefore emerging as a new potential target for treatment of type 2 diabetes and metabolic diseases. Further investigation is however hindered by the lack of suitable receptor modulators. Screening of FFA1 ligands provided a lead with moderate activity on GPR120 and moderate selectivity over FFA1. Optimization led to the discovery of the first potent and selective GPR120 agonist.

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Author and article information

Journal

Journal ID (nlm-ta): ACS Med Chem Lett

Journal ID (iso-abbrev): ACS Med Chem Lett

Journal ID (publisher-id): ml

Journal ID (coden): amclct

Title: ACS Medicinal Chemistry Letters

Publisher: American Chemical Society

ISSN (Print): 1948-5875

ISSN (Electronic): 1948-5875

Publication date (Electronic): 08 April 2013

Publication date (Print): 09 May 2013

Volume: 4

Issue: 5

Pages: 441-445

Affiliations

[† ]Department of Physics, Chemistry and Pharmacy, University of Southern Denmark , Campusvej 55, DK-5230 Odense M, Denmark

[‡ ]Institute of Pharmaceutical and Medicinal Chemistry, University of Düsseldorf , Universitätsstrasse 1, D-40225 Düsseldorf, Germany

[§ ]Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow , Glasgow G12 8QQ, Scotland, U.K.

[∥ ]Clore Laboratory, University of Buckingham , Hunter Street, Buckingham MK18 1EG, U.K.

[⊥ ]Institute of Pharmaceutical Biology, University of Bonn , Nussallee 6, D-53115 Bonn, Germany

[# ]Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology and Clinical Chemistry, University of Tübingen , Otfried-Müller-Str. 10, 72076 Tübingen, Germany

Author notes

[* ](T.U.) E-mail: ulven@ 123456sdu.dk .

Article

DOI: 10.1021/ml4000673

PMC ID: 3654565

PubMed ID: 23687558

SO-VID: de6c62a0-50ae-49e5-bcd3-ab9f976cdba7

History

Date received : 17 February 2013

Date accepted : 08 April 2013

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document-id-old-9 ml4000673

document-id-new-14 ml-2013-000673

ccc-price

ScienceOpen disciplines: Pharmaceutical chemistry

Keywords: type 2 diabetes,free fatty acid receptor,tug-770,insulin secretagogue,ffa1 agonist,gpr40 agonist

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ScienceOpen disciplines: Pharmaceutical chemistry

Keywords: type 2 diabetes, free fatty acid receptor, tug-770, insulin secretagogue, ffa1 agonist, gpr40 agonist

Discovery of TUG-770: A Highly Potent Free Fatty Acid Receptor 1 (FFA1/GPR40) Agonist for Treatment of Type 2 Diabetes

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Most cited references 8

Ligand efficiency: a useful metric for lead selection.

TAK-875 versus placebo or glimepiride in type 2 diabetes mellitus: a phase 2, randomised, double-blind, placebo-controlled trial.

Discovery of a potent and selective GPR120 agonist.

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