The tertiary amine nitrogen atom of piperazine sulfonamides as a novel determinant of potent and selective beta3-adrenoceptor agonists

Novel compounds were prepared in fair to good yields as human beta(3)-adrenoceptor (beta(3)-AR) agonists. In particular, aryloxypropanolamines 7 a-d (EC(50)=0.57-2.1 nM) and arylethanolamines 12 a,b,e (EC(50)=6.38-19.4 nM) were designed to explore the effects of modifications at the right-hand side of these molecules on their activity as beta(3)-AR agonists. Piperidine sulfonamides 15 a-c, e-g (EC(50)=6.1-36.2 nM) and piperazine sulfonamide derivatives 20-29 (EC(50)=1.79-49.3 nM) were examined as compounds bearing a non-aromatic linker on the right- and left-hand sides of the molecules. Some piperazine sulfonamides were found to be potent and selective beta(3)-AR agonists, even if the amine nitrogen atom is tertiary and not secondary, as is the case for all beta(3)-AR agonists reported so far. (S)-3-{4-{N-{4-{2-[2-Hydroxy-3-(4-hydroxyphenoxy)propylamino]ethyl}phenyl}sulfamoyl}phenoxy}propanoic acid (7 d; EC(50)=0.57 nM), (R)-N-{4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenyl}-4-(3-octylureido)benzenesulfonamide (12 e; EC(50)=6.38 nM), (R)-2-[1-(4-methoxyphenylsulfonyl)piperidin-4-ylamino]-1-phenylethanol (15 f; EC(50)=6.1 nM), and (S)-4-{2-hydroxy-3-[4-(4-methoxyphenylsulfonyl)piperazin-1-yl]propoxy}phenol (25; EC(50)=1.79 nM) were found to be the most potent beta(3)-AR agonists of the aryloxypropanolamine, arylethanolamine, piperidine sulfonamide, and piperazine sulfonamide classes, respectively. The two most potent compounds were identified as possible candidates for further development of beta(3)-AR agonists useful in the treatment of beta(3)-AR-mediated pathological conditions.