Screening of a computationally designed synthetic library led to the discovery of the N-phenylphenylglycines (NPPGs) as a novel class of human corticotropin releasing factor (h-CRF1) antagonists. Several NPPGs with greater potency than the original hit 1 were rapidly identified, and resolution of the racemate demonstrated that only the R-enantiomer displays activity. This structural class represents the first example of a non-peptide CRF1 antagonist with a stereochemically distinct receptor binding affinity.