Identification of a novel allosteric GLP-1R antagonist HTL26119 using structure- based drug design

A series of novel allosteric antagonists of the GLP-1 receptor (GLP-1R), exemplified by HTL26119, are described. SBDD approaches were employed to identify HTL26119, exploiting structural understanding of the allosteric binding site of the closely related Glucagon receptor (GCGR) (Jazayeri et al., 2016) and the homology relationships between GCGR and GLP-1R. The region around residue C347(6.36b) of the GLP-1R receptor represents a key difference from GCGR and was targeted for selectivity for GLP-1R.