Transmembrane protein 16A (TMEM16A), also called Ano1, is a Ca(2+) activated Cl(-) channel expressed widely in mammalian epithelia, as well as in vascular smooth muscle and some tumors and electrically excitable cells. TMEM16A inhibitors have potential utility for treatment of disorders of epithelial fluid and mucus secretion, hypertension, some cancers and other diseases. 4-Aryl-2-amino thiazole T16Ainh-01 was previously identified by high-throughput screening. Here, a library of 47 compounds were prepared that explored the 5,6-disubstituted pyrimidine scaffold found in T16Ainh-01. TMEM16A inhibition activity was measured using fluorescence plate reader and short-circuit current assays. We found that very little structural variation of T16Ainh-01 was tolerated, with most compounds showing no activity at 10 μM. The most potent compound in the series, 9bo, which substitutes 4-methoxyphenyl in T16Ainh-01 with 2-thiophene, had IC50 ∼1 μM for inhibition of TMEM16A chloride conductance.