2. Academic Validation
  3. Discovery and Optimization of Novel SUCNR1 Inhibitors: Design of Zwitterionic Derivatives with a Salt Bridge for the Improvement of Oral Exposure

Discovery and Optimization of Novel SUCNR1 Inhibitors: Design of Zwitterionic Derivatives with a Salt Bridge for the Improvement of Oral Exposure

  • J Med Chem. 2020 Sep 10;63(17):9856-9875. doi: 10.1021/acs.jmedchem.0c01020.
Juraj Velcicky 1,  Rainer Wilcken 1,  Simona Cotesta 1,  Philipp Janser 1,  Achim Schlapbach 1,  Trixie Wagner 1,  Philippe Piechon 1,  Frederic Villard 1,  Rochdi Bouhelal 1,  Fabian Piller 1,  Stephanie Harlfinger 1,  Rowan Stringer 1,  Dominique Fehlmann 1,  Klemens Kaupmann 1,  Amanda Littlewood-Evans 1,  Matthias Haffke 1,  Nina Gommermann 1
Affiliations

Affiliation

  • 1 Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
PMID: 32856916 DOI: 10.1021/acs.jmedchem.0c01020
Abstract

G-protein-coupled receptor SUCNR1 (Succinate Receptor 1 or GPR91) senses the citric cycle intermediate succinate and is implicated in various pathological conditions such as rheumatoid arthritis, liver fibrosis, or obesity. Here, we describe a novel SUCNR1 antagonist scaffold discovered by high-throughput screening. The poor permeation and absorption properties of the most potent compounds, which were zwitterionic in nature, could be improved by the formation of an internal salt bridge, which helped in shielding the two opposite charges and thus also the high polarity of zwitterions with separated charges. The designed compounds containing such a salt bridge reached high oral bioavailability and oral exposure. We believe that this principle could find a broad interest in the medicinal chemistry field as it can be useful not only for the modulation of properties in zwitterionic compounds but also in acidic or basic compounds with poor permeation.

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