Ernesto Santandrea

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 β3‐adrenoceptor (β3‐AR) agonists. In particular, aryloxypropanolamines 7 a–d (EC50=0.57–2.1 nM) and arylethanolamines 12 a,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 β3‐AR agonists. Piperidine sulfonamides 15 a–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 β3‐AR agonists, even if the amine nitrogen atom is tertiary and not secondary, as is the case for all β3‐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; EC50=0.57 nM), (R)‐N‐{4‐[2‐(2‐hydroxy‐2‐phenylethylamino)ethyl]phenyl}‐4‐(3‐octylureido)benzenesulfonamide (12 e; EC50=6.38 nM), (R)‐2‐[1‐(4‐methoxyphenylsulfonyl)piperidin‐4‐ylamino]‐1‐phenylethanol (15 f; EC50=6.1 nM), and (S)‐4‐{2‐hydroxy‐3‐[4‐(4‐methoxyphenylsulfonyl)piperazin‐1‐yl]propoxy}phenol (25; EC50=1.79 nM) were found to be the most potent β3‐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 β3‐AR agonists useful in the treatment of β3‐AR‐mediated pathological conditions.