Novel Macrocyclic Antagonists of the Calcitonin Gene-Related Peptide Receptor: Design, Realization, and Structural Characterization of Protein-Ligand Complexes.
Andrew D CansfieldMark A AtorJoydeep BanerjeeMichael BestwickAndrea BortolatoGiles A BrownJason BrownKristina ButkovicJulie E CansfieldJohn A ChristopherMiles CongreveGabriella CsekeFrancesca DeflorianBenjamin DuganMartina Petrovic HunjadiAntun HutinecTrinadh Kumar InturiGoran LandekJonathan MasonM Alistair O'BrienGregory R OttRenata RupcicGordon SaxtyStacey M SouthallRahela ZadravecStephen P WatsonPublished in: ACS chemical neuroscience (2022)
A series of macrocyclic calcitonin gene-related peptide (CGRP) receptor antagonists identified using structure-based design principles, exemplified by HTL0028016 ( 1 ) and HTL0028125 ( 2 ), is described. Structural characterization by X-ray crystallography of the interaction of two of the macrocycle antagonists with the CGRP receptor ectodomain is described, along with structure-activity relationships associated with point changes to the macrocyclic antagonists. The identification of non-peptidic/natural product-derived, macrocyclic ligands for a G protein coupled receptor (GPCR) is noteworthy.