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Although several PPI inhibitors with improved selectivity have recently been identified, using combined approaches that brought together protein crystallography, ligand NMR spectroscopy, and computational chemistry, unfortunately, none of them has been found to be able to cross the BBB and many are quite large in size and contain carboxylic acids, features which usually prevent or decrease CNS permeability [299]

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This D-amino acid substitution introduces conformational rigidity within the pharmacophore core (His-D-Phe-Arg-Trp) and significantly increases binding affinity across melanocortin receptor subtypes compared to both -MSH and MT-1

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