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.

2022-03-16·ACS Chemical Neuroscience3区 · 医学

Novel Macrocyclic Antagonists of the Calcitonin Gene-Related Peptide Receptor: Design, Realization, and Structural Characterization of Protein–Ligand Complexes

3区 · 医学

Article

作者: Banerjee, Joydeep ; Dugan, Benjamin ; Watson, Stephen P. ; Cseke, Gabriella ; Hutinec, Antun ; Landek, Goran ; Southall, Stacey M. ; Butkovic, Kristina ; Congreve, Miles ; Deflorian, Francesca ; Saxty, Gordon ; Inturi, Trinadh Kumar ; Ator, Mark A. ; Cansfield, Andrew D. ; Christopher, John A. ; Brown, Giles A. ; Hunjadi, Martina Petrovic ; Mason, Jonathan ; Bortolato, Andrea ; Zadravec, Rahela ; Brown, Jason ; O’Brien, Alistair ; Ott, Gregory R. ; Cansfield, Julie E. ; Rupcic, Renata ; Bestwick, Michael

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.

100 项与 HTL-0029881 相关的药物交易

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