Novel macrocyclic antagonists of the calcitonin gene-related peptide receptor: design, realization, and structural characterization of protein–ligand complexes

DOI: 10.1021/acschemneuro.1c00696

Authors: Andrew D. Cansfield (Sosei Heptares) , Mark A. Ator (Teva Pharmaceuticals) , Joydeep Banerjee (Syngene International) , Michael Bestwick (Sosei Heptares) , Andrea Bortolato (Sosei Heptares) , Giles A. Brown (Sosei Heptares) , Jason Brown (Sosei Heptares) , Kristina Butkovic (Fidelta d.o.o.) , Julie E. Cansfield (Sosei Heptares) , John A. Christopher (Sosei Heptares) , Miles Congreve (Sosei Heptares) , Gabriella Cseke (Sosei Heptares) , Francesca Deflorian (Sosei Heptares) , Benjamin Dugan (Teva Pharmaceuticals) , Martina Petrovic Hunjadi (Fidelta d.o.o.) , Antun Hutinec (Fidelta d.o.o.) , Trinadh Kumar Inturi (Syngene International) , Goran Landek (Fidelta d.o.o.) , Jonathan Mason (Sosei Heptares) , Alistair O’brien (Sosei Heptares) , Gregory R. Ott (Teva Pharmaceuticals) , Renata Rupcic (Fidelta d.o.o.) , Gordon Saxty (Fidelta d.o.o.) , Stacey M. Southall (Sosei Heptares) , Rahela Zadravec (Fidelta d.o.o.) , Stephen P. Watson (Sosei Heptares)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Acs Chemical Neuroscience , VOL 96

State: Published (Approved)
Published: March 2022

Abstract: 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.

Journal Keywords: GPCR; CGRP; CGRPR; macrocycle; macrocyclic; antagonist

Diamond Keywords: Migraine

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I24-Microfocus Macromolecular Crystallography

Added On: 07/03/2022 08:54

Discipline Tags:

Health & Wellbeing Biochemistry Neurology Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)