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
The IC50 of a beta-secretase (BACE-1) lead compound was improved â¼200-fold from 11 µM to 55 nM through the addition of a single methyl group. Computational chemistry, small molecule NMR, and protein crystallography capabilities were used to compare the solution conformation of the ligand under varying pH conditions to its conformation when bound in the active site. Chemical modification then explored available binding pockets adjacent to the ligand. A strategically placed methyl group not only maintained the required pKa of the piperidine nitrogen and filled a small hydrophobic pocket, but more importantly, stabilized the conformation best suited for optimized binding to the receptor.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Hydantoins/chemistry , Hydantoins/pharmacology , Amyloid Precursor Protein Secretases/metabolism , Aspartic Acid Endopeptidases/metabolism , Crystallography, X-Ray , Dose-Response Relationship, Drug , Humans , Hydantoins/chemical synthesis , Methylation , Models, Molecular , Molecular Structure , 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.
Subject(s)
Alkenes/pharmacology , Calcitonin Gene-Related Peptide Receptor Antagonists , Alkenes/chemical synthesis , Alkenes/chemistry , Amides/chemistry , Dose-Response Relationship, Drug , HEK293 Cells , Humans , Molecular Structure , Structure-Activity RelationshipABSTRACT
Rational modification of the potent calcitonin gene-related peptide (CGRP) receptor antagonist MK-3207 led to a series of analogues with enhanced CNS penetrance and a convenient chemical handle for introduction of a radiolabel. A number of (11)C-tracers were synthesized and evaluated in vivo, leading to the identification of [(11)C]8 ([(11)C]MK-4232), the first positron emission tomography tracer for the CGRP receptor.
