Novel Macrocyclic Antagonists of the CGRP Receptor Part 2: Stereochemical Inversion Induces an Unprecedented Binding Mode

Stacey M Southall; Joydeep Banerjee; Jason Brown; Kristina Butkovic; Andrew D Cansfield; Julie E Cansfield; Miles S Congreve; Gabriella Cseke; Francesca Deflorian; Martina Petrovic Hunjadi; Antun Hutinec; Trinadh Kumar Inturi; Renata Rupcic; Gordon Saxty; Stephen P Watson

doi:10.1021/acsmedchemlett.2c00400

Novel Macrocyclic Antagonists of the CGRP Receptor Part 2: Stereochemical Inversion Induces an Unprecedented Binding Mode

ACS Med Chem Lett. 2022 Oct 19;13(11):1776-1782. doi: 10.1021/acsmedchemlett.2c00400. eCollection 2022 Nov 10.

Authors

Affiliations

¹ Sosei Heptares, Steinmetz Building, Granta Park, Great Abington, Cambridge CB21 6DG, United Kingdom.
² Syngene International, Biocon Park, Bommasandra, Bangalore, Karnataka 560099, India.
³ Selvita d.o.o., Prilaz aruna Filipovića 29, 10000 Zagreb, Croatia.

Abstract

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.