Article
作者: Brown, Jason ; Hunjadi, Martina Petrovic ; Butkovic, Kristina ; Deflorian, Francesca ; Cansfield, Julie E. ; Inturi, Trinadh Kumar ; Rupcic, Renata ; Watson, Stephen P. ; Cseke, Gabriella ; Banerjee, Joydeep ; Southall, Stacey M. ; Congreve, Miles S. ; Saxty, Gordon ; Cansfield, Andrew D. ; Hutinec, Antun
The diastereomeric macrocyclic calcitonin gene-related peptide (CGRP) antagonists HTL0029881 (3) and HTL0029882 (4), in which the stereochemistry of a spiro center is reversed, surprisingly demonstrate comparable potency. X-ray crystallographic characterization demonstrates that 3 binds to the CGRP receptor in a precedented manner but that 4 binds in an unprecedented, unexpected, and radically different manner. The observation of this phenomenon is noteworthy and may open novel avenues for CGRP receptor antagonist design.