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

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

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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