2-Amino-4-benzyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridines: Novel Selective β3-Adrenoceptor Agonists

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Abstract
Trimetoquinol (TMQ, 7) is a potent nonselective β-adrenoceptor (AR) agonist. Replacement of the catechol moiety of TMQ with a 2-aminothiazole group resulted in novel thiazolopyridine derivatives 9−11 which have been synthesized and evaluated for biological activity on human β1-, β2-, and β3-AR. The Bischler−Napieralski reaction has been employed as a novel approach to construct the 2-amino-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine ring system. Although in radioligand binding studies analogues 9 and 10 did not show selectivity toward β3-AR, they exhibited a high degree of selective β3-AR agonist activity in functional assays. Moreover, the β3-AR agonist activity of the 2-aminothiazole derivatives is abolished by N-acetylation (analogue 11) or ring opening (analogue 25). This illustrates the importance of the intact 2-amino-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine ring for β3-AR activity.