12. The Dompé Farmaceutici TRPM8 blocker, compound 59 is a potent (IC50 = 11 nM) compound for painful ocular conditions, with ocular efficacy in a preclinical behavioral model. TRPM8 is a cation channel which is the predominant in mammalian cold thermosensor and it is activated by well-known molecules like menthol, eucalyptol, and geraniol. The starting points were previous drug candidates tetrazole DFL23448 and ketone DFL23693. The molecule possesses an unusual hydroxythiazole which was found to be critical for activity. An unusual N-alkoxy amide was also employed, with surprisingly sharp SAR. The compound shows rapid activity in a preclinical model (15 min post dose) and is an rare case study for ocular drug discovery.