2. Academic Validation
  3. Development of Selective, Orally Active GPR4 Antagonists with Modulatory Effects on Nociception, Inflammation, and Angiogenesis

Development of Selective, Orally Active GPR4 Antagonists with Modulatory Effects on Nociception, Inflammation, and Angiogenesis

  • J Med Chem. 2017 May 11;60(9):3672-3683. doi: 10.1021/acs.jmedchem.6b01703.
Juraj Velcicky 1,  Wolfgang Miltz 1,  Berndt Oberhauser 1,  David Orain 1,  Andrea Vaupel 1,  Klaus Weigand 1,  Janet Dawson King 1,  Amanda Littlewood-Evans 1,  Mark Nash 1,  Roland Feifel 1,  Pius Loetscher 1
Affiliations

Affiliation

  • 1 Global Discovery Chemistry, ‡Autoimmunity Transplantation Inflammation, §Musculoskeletal, ∥Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research , CH-4002 Basel, Switzerland.
PMID: 28445047 DOI: 10.1021/acs.jmedchem.6b01703
Abstract

A novel, selective, and efficacious GPR4 Antagonist 13 was developed starting from lead compound 1a. While compound 1a showed promising efficacy in several disease models, its binding to a H3 receptor as well as a hERG channel prevented it from further development. Therefore, a new round of optimization addressing the key liabilities was performed and led to discovery of compound 13 with an improved profile. Compound 13 showed significant efficacy in the rat antigen induced arthritis as well as in the hyperalgesia and angiogenesis model at a well-tolerated dose of 30 mg/kg.

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