Design and synthesis of potent and orally active GPR4 antagonists with modulatory effects on nociception, inflammation, and angiogenesis

  • Bioorg Med Chem. 2017 Aug 15;25(16):4512-4525. doi: 10.1016/j.bmc.2017.06.050.
Wolfgang Miltz  1 ,  Juraj Velcicky  2 ,  Janet Dawson  3 ,  Amanda Littlewood-Evans  3 ,  Marie-Gabrielle Ludwig  4 ,  Klaus Seuwen  4 ,  Roland Feifel  5 ,  Berndt Oberhauser  2 ,  Arndt Meyer  2 ,  Daniela Gabriel  4 ,  Mark Nash  6 ,  Pius Loetscher  3
Affiliations
  • 1. Global Discovery Chemistry, Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland. Electronic address: [email protected].
  • 2. Global Discovery Chemistry, Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
  • 3. Autoimmunity, Transplantation and Inflammation, Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
  • 4. Chemical Biology and Therapeutics, Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
  • 5. PK Sciences, Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
  • 6. Muscoloskeletal Diseases, Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
PMID: 28689977 DOI: 10.1016/j.bmc.2017.06.050
Abstract

GPR4, a G-protein coupled receptor, functions as a proton sensor being activated by extracellular acidic pH and has been implicated in playing a key role in acidosis associated with a variety of inflammatory conditions. An orally active GPR4 Antagonist 39c was developed, starting from a high throughput screening hit 1. The compound shows potent cellular activity and is efficacious in animal models of angiogenesis, inflammation and pain.

Keywords
Amino-pyrimidine derivatives; Angiogenesis; GPR4; Imidazo-pyridine derivatives; Inflammation; Pain.