Background: The metalloproteinases ADAM10 and ADAM17 are involved in various diseases: neurodegeneration, cancer and inflammation. Objective: The inhibition of these proteases is a promising target in the treatment of inflammation and cancer. Methods and Results: In this study, we present an improved synthesis of the ADAM10 reference inhibitor GI254023X with a higher overall yield, enhanced detection ability and increased acid stability, providing easier handling. Conclusion: This upscaled synthesis, free of diastereomeric intermediates, ensures single-batch identity, thus warranting its reproducibility in further biological investigations.