Discovery and in vitro Characterization of BAY 2686013, an Allosteric Small Molecule Antagonist of the Human PAC1 Receptor.

Abstract

The human pituitary adenylate cyclase activating polypeptide receptor (hPAC1-R), a class B GPCR identified almost 30 years ago, represents an important pharmacological target in the areas of neuroscience, oncology, and immunology. Despite interest in this target, only a very limited number of small molecule modulators have been reported for this receptor. We herein describe the results of a drug discovery program aiming for the identification of a potent and selective hPAC1-R antagonist. An initial HTS screen of 3.05 million compounds originating from the Bayer screening library failed to identify any tractable hits. A second, completely revised screen using native HEK293 cells yielded a small number of hits exhibiting antagonistic properties (4.2 million compounds screened). BAY 2686013 (1) emerged as a promising compound showing selective antagonistic activity in the sub-micromolar potency range. In depth characterization supported the hypothesis that BAY 2686013 blocks receptor activity in a non-competitive manner. Preclinical, pharmacokinetic profiling indicates that BAY 2686013 is a valuable tool compound for better understanding the signalling and function of hPAC1-R. Significance Statement Although the human PAC1-R is of major significance as a therapeutic target with a well-documented role in pain signaling, only a very limited number of small molecule (SMOL) compounds are known to modulate its activity. We identified and thoroughly characterized a novel, potent and selective SMOL antagonist of hPAC1-R (acting in an allosteric manner). These characteristics make BAY 2686013 an ideal tool for further studies.