ABSTRACT
In our efforts to develop CGRP receptor antagonists as backups to MK-3207, 2, we employed a scaffold hopping approach to identify a series of novel oxazolidinone-based compounds. The development of a structurally diverse, potent (20, cAMP+HS IC50=0.67 nM), and selective compound (hERG IC50=19 µM) with favorable rodent pharmacokinetics (F=100%, t1/2=7h) is described. Key to this development was identification of a 3-substituted spirotetrahydropyran ring that afforded a substantial gain in potency (10 to 35-fold).
Subject(s)
Calcitonin Gene-Related Peptide Receptor Antagonists , Migraine Disorders/drug therapy , Oxazolidinones/pharmacology , Oxazolidinones/therapeutic use , Animals , Dose-Response Relationship, Drug , Humans , Molecular Docking Simulation , Molecular Structure , Oxazolidinones/chemical synthesis , Oxazolidinones/chemistry , Rats , Structure-Activity RelationshipABSTRACT
A new class of CGRP receptor antagonists was identified by replacing the central amide of a previously identified anilide lead structure with ethylene, ethane, or ethyne linkers. (E)-Alkenes as well as alkynes were found to preserve the proper bioactive conformation of the amides, necessary for efficient receptor binding. Further exploration resulted in several potent compounds against CGRP-R with low susceptibility to P-gp mediated efflux.
