Novel Macrocyclic Antagonists of the CGRP Receptor Part 2: Stereochemical Inversion Induces an Unprecedented Binding Mode
ACS Medicinal Chemistry Letters(2022)
摘要
The diastereomeric macrocyclic calcitonin gene-related peptide (CGRP) antagonists HTL0029881 () and HTL0029882 (), in which the stereochemistry of a spiro center is reversed, surprisingly demonstrate comparable potency. X-ray crystallographic characterization demonstrates that binds to the CGRP receptor in a precedented manner but that 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.
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关键词
GPCR, CGRP, CGRPR, Macrocycle, Macrocyclic, Antagonist
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