2-amino-4-benzyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridines: Novel selective beta(3)-adrenoceptor agonists

Trimetoquinol (TMQ, 7) is a potent nonselective beta-adrenoceptor (AR) agon ist. Replacement of the catechol moiety of TMQ with a 2-aminothiazole group resulted in novel thiazolopyridine derivatives 9-11 which have been synthe sized and evaluated for biological activity on human beta(1)-, beta(2)-, an d beta(3)-AR. The Bisckler-Napieralski reaction has been employed as a nove l approach to construct the 2-amino-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridi ne ring system. Although in radioligand binding studies analogues 9 and 10 did not show selectivity toward beta(3)-AR, they exhibited a high degree of selective beta(3)-AR agonist activity in functional assays. Moreover, the beta(3)-AR agonist activity of the 2-aminothiazole derivatives is abolished by N-acetylation (analogue 11) or ring opening (analogue 25). This illustr ates the importance of the intact 2-amino-4,5,6,7-tetrahydrothiazolo[5,4-c] pyridine ring for beta(3)-AR activity.