Human lipoxygenases (LOXs) are enzymes involved in catalyzing the oxidation of polyunsaturated fatty acids to provide the corresponding bioactive hydroxyeicosatetraenoic acid (HETE) metabolites as the end product [1-3]. These eicosanoid signaling molecules are involved in a number of physiologic responses such as platelet aggregation, inflammation and cell proliferation [4-6]. As a result, modulation of these responses through the inhibition of the lipoxygenase enzymes is of great interest. Our group has particular interest in platelet-type 12-(S)-LOX (12-LOX) because of its demonstrated role in skin diseases, diabetes, platelet hemostasis, thrombosis and cancer [7-11]. However, despite the potential of 12-LOX as a therapeutic target, few potent and selective inhibitors have been reported. The lack of high quality 12-LOX inhibitors prompted us to initiate a high-throughput screening campaign as part of the MLPCN program which ultimately led to the discovery of ML127. While potent and selective, ML127 demonstrated limited tolerance for structural modifications, which hampered continued medicinal chemistry efforts thus a continued discovery efforts to develop additional novel inhibitors of 12-LOX is needed. Herein, we report the identification and medicinal chemistry optimization of an unrelated, second chemotype, ML355, which displays nM potency against 12-LOX and excellent selectivity over related lipoxygenases and cyclooxygenases. ML355 has favorable absorption, distribution, metabolism, and excretion (ADME) properties, inhibits PAR-4 induced aggregation and calcium mobilization in human platelets, and reduces 12-HETE in mouse/human beta cells suggesting its potential utility in animal models for antiplatelet therapy and diabetes.