Identification and synthesis of 2,7-diamino-thiazolo[5,4-d]pyrimidine derivatives as TRPV1 antagonists

We have identified and synthesized a series of 2,7-diamino-thiazolo[5,4-d]pyrimidines as TRPV1 antagonists. An exploration of the structure–activity relationships at the 2-, 5-, and 7-positions of the thiazolo[5,4-d]pyrimidine led to the identification of several potent TRPV1 antagonists, including 3, 29, 51, and 57. Compound 3 was orally bioavailable and afforded a significant reversal of carrageenan-induced thermal hyperalgesia with an ED50 = 0.5 mg/kg in rats.

Graphical abstractThe identification and synthesis of 2,7-diamino-thiazolo[5,4-d]pyrimidines as TRPV1 antagonists is described. An exploration of the structure–activity relationships at the 2-, 5-, and 7-positions of the thiazolo[5,4-d]pyrimidine led to the identification of several highly potent TRPV1 antagonists, including 3. Compound 3 was orally bioavailable and afforded a significant reversal of carrageenan-induced thermal hyperalgesia.Figure optionsDownload full-size imageDownload as PowerPoint slide