2. Academic Validation
  3. Discovery and development of CPL207280 as new GPR40/FFA1 agonist

Discovery and development of CPL207280 as new GPR40/FFA1 agonist

  • Eur J Med Chem. 2021 Dec 15:226:113810. doi: 10.1016/j.ejmech.2021.113810.
Mateusz Mach 1,  Katarzyna Bazydło-Guzenda 2,  Paweł Buda 3,  Mikołaj Matłoka 3,  Radosław Dzida 3,  Filip Stelmach 3,  Kinga Gałązka 3,  Małgorzata Wąsińska-Kałwa 3,  Damian Smuga 3,  Dagmara Hołowińska 3,  Urszula Dawid 3,  Lidia Gurba-Bryśkiewicz 3,  Krzysztof Wiśniewski 3,  Krzysztof Dubiel 3,  Jerzy Pieczykolan 3,  Maciej Wieczorek 3
Affiliations

Affiliations

  • 1 Celon Pharma S.A., R&D Centre, Marymoncka 15, 05-152, Kazun Nowy, Poland. Electronic address: mateusz.mach@celonpharma.com.
  • 2 Celon Pharma S.A., R&D Centre, Marymoncka 15, 05-152, Kazun Nowy, Poland; Postgraduate School of Molecular Medicine, Medical University of Warsaw, 61 Zwirki i Wigury Street, 02-091, Warsaw, Poland.
  • 3 Celon Pharma S.A., R&D Centre, Marymoncka 15, 05-152, Kazun Nowy, Poland.
PMID: 34537444 DOI: 10.1016/j.ejmech.2021.113810
Abstract

Due to a unique mechanism that limits the possibility of hypoglycemia, the Free Fatty Acid Receptor (FFA1) is an attractive target for the treatment of type 2 diabetes. So far, however, none of the promising agonists have been able to enter the market. The most advanced clinical candidate, TAK-875, was withdrawn from phase III clinical trials due to liver safety issues. In this article, we describe the key aspects leading to the discovery of CPL207280 (13), the design of which focused on long-term safety. The introduction of small, nature-inspired acyclic structural fragments resulted in compounds with retained high potency and a satisfactory pharmacokinetic profile. Optimized synthesis and upscaling provided a stable, solid form of CPL207280-51 (45) with the properties required for the toxicology studies and ongoing clinical trials.

Keywords

Agonist; CPL207280; Diabetes; FFA1; GPR40; GSIS; Insulin; T2D.

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