• Biomolecules & Therapeutics
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• v.12 no.4
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• pp.215-220
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• 2004

In an attempt to develop new anti-diabetic agents, a series of aryloxypropanolamine derivatives was synthesized to serve as ${\beta}_3$ adrenoceptor agonists. Among these derivatives, 1-{1-methyl-3-[4-(2-methyl-2H-1,2,3,4-tetrazol-5-yl)phenyl]propylamino}-3-phenoxy-2-propanol (KR60886) possessed a high affinity for the ${\beta}_3$ adrenoceptor (Ki = 28 nM) and moderate affinities for ${\beta}_1$ and ${\beta}_2$ adrenoceptors (Ki = 95 nM and 100 nM, respectively). In addition, KR60886 stimulated cAMP production with an EC$_{50}$ of 0.4 ${\mu}M$, confirming its agonistic activity for the ${\beta}_3$ adrenoceptor. In vivo activities of KR60886 were examined by using a fat-fed/streptozotocin (STZ)-treated rat model and the ob/ob mouse model. Oral administration of KR60886 (10 mg/kg) for 3 days (b.i.d.) to fat-fed/STZ-treated rats significantly lowered plasma glucose levels and reduced plasma free fatty acid concentrations. Similarly, KR60886 treatment (10 mg/kg/day for 7 d) resulted in a reduction of plasma glucose concentrations in ob/ob mice. The present study suggests that KR60886 is a potent ${\beta}_3$ receptor agonist with in vivo anti-diabetic properties.