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

Wolfgang Miltz; Juraj Velcicky; Janet Dawson; Amanda Littlewood-Evans; Marie-Gabrielle Ludwig; Klaus Seuwen; Roland Feifel; Berndt Oberhauser; Arndt Meyer; Daniela Gabriel; Mark Nash; Pius Loetscher

doi:10.1016/j.bmc.2017.06.050

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. Epub 2017 Jun 29.

Authors

Affiliations

¹ Global Discovery Chemistry, Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland. Electronic address: wolfgang.miltz@novartis.com.
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.

MeSH terms

Administration, Oral
Animals
Anti-Inflammatory Agents, Non-Steroidal / administration & dosage
Anti-Inflammatory Agents, Non-Steroidal / chemistry
Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
Arthritis / drug therapy
Arthritis / metabolism
COS Cells
Chlorocebus aethiops
Dose-Response Relationship, Drug
Drug Design*
Female
HEK293 Cells
HeLa Cells
Humans
Inflammation / drug therapy*
Inflammation / metabolism
Mice
Molecular Structure
Pain / drug therapy
Pain / metabolism
Rats
Rats, Sprague-Dawley
Receptors, G-Protein-Coupled / antagonists & inhibitors*
Receptors, G-Protein-Coupled / metabolism
Structure-Activity Relationship

Substances

Anti-Inflammatory Agents, Non-Steroidal
GPR4 protein, human
Receptors, G-Protein-Coupled