Inhibition of plasmin has been found to effectively reduce fibrinolysis and to avoid hemorrhage. This can be achieved by addressing its kringle 1 domain with the known drug and lysine analogue tranexamic acid. Guided by shape similarities toward a previously discovered lead compound, 5-(4-piperidyl)isoxazol-3-ol, a set of 16 structurally similar compounds was assembled and investigated. Successfully, in vitro measurements revealed one compound, 5-(4-piperidyl)isothiazol-3-ol, superior in potency compared to the initial lead. Furthermore, a strikingly high correlation (R2 = 0.93) between anti-fibrinolytic activity and kringle 1 binding affinity provided strong support for the hypothesized inhibition mechanism, as well as revealing opportunities to fine-tune biological effects through minor structural modifications. Several different ligand-based (Freeform, shape, and electrostatic-based similarities) and structure-based methods (e.g., Posit, MM/GBSA, FEP+) were used to retrospectively predict the binding affinities. A combined method, molecular alignment using Posit and scoring with Tcombo, lead to the highest coefficient of determination (R2 = 0.6).