2. Academic Validation
  3. Identification of novel GPR81 agonist lead series for target biology evaluation

Identification of novel GPR81 agonist lead series for target biology evaluation

  • Bioorg Med Chem Lett. 2020 Feb 15;30(4):126953. doi: 10.1016/j.bmcl.2020.126953.
Öjvind Davidsson 1,  Kristina Nilsson 2,  Jonas Brånalt 3,  Terese Andersson 4,  Kristina Berggren 5,  Yantao Chen 3,  Ola Fjellström 6,  Henrik Gradén 3,  Linda Gustafsson 3,  Nils-Olov Hermansson 7,  Frank Jansen 8,  Petra Johannesson 9,  Bengt Ohlsson 3,  Christian Tyrchan 5,  Annika Wellner 5,  Eric Wellner 3,  Maria Ölwegård-Halvarsson 3
Affiliations

Affiliations

  • 1 CVRM Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden. Electronic address: ojvind.davidsson@astrazeneca.com.
  • 2 CVRM Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden. Electronic address: kristina.a.nilsson@astrazeneca.com.
  • 3 CVRM Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
  • 4 CVRM Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; Early Product Development, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
  • 5 CVRM Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; RIA Medicinal Chemistry, Research and Early Development, Respiratory, Inflammation and Autoimmune, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
  • 6 CVRM Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
  • 7 Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden.
  • 8 Mechanistic Biology & Profiling, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden.
  • 9 CVRM Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; Global Patient Safety CVRM, Chief Medical Office, AstraZeneca R&D, Gothenburg, Sweden.
PMID: 31932225 DOI: 10.1016/j.bmcl.2020.126953
Abstract

GPR81 is a novel drug target that is implicated in the control of glucose and lipid metabolism. The lack of potent GPR81 modulators suitable for in vivo studies has limited the pharmacological characterization of this lactate sensing receptor. We performed a high throughput screen (HTS) and identified a GPR81 agonist chemical series containing a central acyl urea scaffold linker. During SAR exploration two additional new series were evolved, one containing cyclic acyl urea bioisosteres and another a central amide bond. These three series provide different selectivity and physicochemical properties suitable for in-vivo studies.

Keywords

GHSR1a; GPCR; GPR109A; GPR81; HTS; Lipolysis.

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