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The Tertiary Amine Nitrogen Atom of Piperazine Sulfonamides as a Novel Determinant of Potent and Selective β 3 ‐Adrenoceptor Agonists
Author(s) -
Perrone Maria Grazia,
Bleve Laura,
Santandrea Ernesto,
Vitale Paola,
Niso Mauro,
Scilimati Antonio
Publication year - 2009
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200900292
Subject(s) - piperazine , piperidine , sulfonamide , chemistry , propanoic acid , amine gas treating , tertiary amine , stereochemistry , molecule , medicinal chemistry , morpholine , organic chemistry
Novel compounds were prepared in fair to good yields as human β 3 ‐adrenoceptor (β 3 ‐AR) agonists. In particular, aryloxypropanolamines 7 a – d (EC 50 =0.57–2.1 n M ) and arylethanolamines 12 a , b , e (EC 50 =6.38–19.4 n M ) were designed to explore the effects of modifications at the right‐hand side of these molecules on their activity as β 3 ‐AR agonists. Piperidine sulfonamides 15 a – c , e – g (EC 50 =6.1–36.2 n M ) and piperazine sulfonamide derivatives 20 – 29 (EC 50 =1.79–49.3 n M ) 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 β 3 ‐AR agonists, even if the amine nitrogen atom is tertiary and not secondary, as is the case for all β 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 n M ), ( R )‐ N ‐{4‐[2‐(2‐hydroxy‐2‐phenylethylamino)ethyl]phenyl}‐4‐(3‐octylureido)benzenesulfonamide ( 12 e ; EC 50 =6.38 n M ), ( R )‐2‐[1‐(4‐methoxyphenylsulfonyl)piperidin‐4‐ylamino]‐1‐phenylethanol ( 15 f ; EC 50 =6.1 n M ), and ( S )‐4‐{2‐hydroxy‐3‐[4‐(4‐methoxyphenylsulfonyl)piperazin‐1‐yl]propoxy}phenol ( 25 ; EC 50 =1.79 n M ) were found to be the most potent β 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 β 3 ‐AR agonists useful in the treatment of β 3 ‐AR‐mediated pathological conditions.