This report describes the high throughput screening (HTS) screening and optimization of a lead series of severe acute respiratory syndrome (SARS) main proteinase 3CLpro inhibitors leading to the identification of ML188, ((R)-N-(4-(tert-butyl)phenyl)-N-(2-(tert-butylamino)-2-oxo-1-(pyridin-3-yl)ethyl)furan-2-carboxamide, CID 46897844). ML188 represents the first true non-covalent 3CLpro inhibitor with modest molecular weight (MW) and good inhibitory activity below 2 μM. An Ugi reaction was utilized to rapidly explore structure activity relationship (SAR) and x-ray crystallography using inhibitor bound 3CLpro structures was instrumental in guiding chemistry optimization. This report and probe herein will allow others in the field access to new starting points for 3CLpro inhibitor design and optimization.