The Tertiary Amine Nitrogen Atom of Piperazine Sulfonamides as a Novel Determinant of Potent and Selective β3-Adrenoceptor Agonists

Novel compounds were prepared in fair to good yields as human beta(3)-adrenoceptor (beta(3)-AR) agonists. In particular, aryloxypropanolamines 7a-d (EC50=0.57-2.1 nm) and arylethanolamines 12a,b,e (EC50=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 15a-c,e-g (EC50=6.1-36.2 nm) and piperazine sulfonamide derivatives 20-29 (EC50=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 (7d; EC50=0.57 nM), (R)-N-{4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenyl}-4-(3-octyl-ureido)benzenesulfonamide (12e; EC50=6.38 nm), (R)-2-[1-(4-methoxyphenylsulfonyl)piperidin-4-ylamino]-1-phenylethanol (15f; EC50=6.1 nm), and (S)-4-{2-hydroxy-3-[4-(4-methoxyphenylsulfonyl)piperazin-1-yl]propoxy}pheno; (25; EC50=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.