Synthesis and evaluation of potent and selective beta(3) adrenergic receptor agonists containing acylsulfonamide, sulfonylsulfonamide, and sulfonylurea carboxylic acid isosteres.
Starting from phenethanolamine aniline leads 3a and 3b, we have identified a series of functionally potent and selective beta(3) adrenergic receptor (AR) agonists containing acylsulfonamide, sulfonylsulfonamide, or sulfonylurea groups within the aniline phenethanolamine series. In beta(3), beta(2), and beta(1) AR cAMP functional assays, 3a and other right-hand side (RHS) carboxylate analogues were found to be full agonists that were modestly selective against beta(1) or beta(2) ARs, while analogues lacking RHS acid functionality were active at beta(3) AR but not selective. Replacement of the carboxylate with acylthiazole and acylmethylsulfone gave potent, but only modestly selective, compounds. Increasing the size of the RHS sulfonamide substituent with phenyl or p-toluene afforded compounds with good potency and functional selectivity (beta(3) AR pEC(50) greater than 8; beta(1) and beta(2) AR selectivity greater than 40- and 500-fold, respectively). Our SAR studies suggest that the potency and selectivity profile of the best analogues reported here is a result of both the steric bulk and acidity of the RHS sulfonamide NH group. Although all of the analogues had a pharmacokinetic half-life of less than 2 h, acylsulfonamides 43 and 44 did show moderately low clearance in dogs. These two compounds were further evaluated by thermographic imaging in mice and were found to produce a robust thermogenic response via oral administration.
Uehling
David E
DE
Department of Medicinal Chemistry, GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA. deu8774@gsk.com
Donaldson
Kelly H
KH
Deaton
David N
DN
Hyman
Clifton E
CE
Sugg
Elizabeth E
EE
Barrett
David G
DG
Hughes
Robert G
RG
Reitter
Barbara
B
Adkison
Kim K
KK
Lancaster
Mary E
ME
Lee
Frank
F
Hart
Robert
R
Paulik
Mark A
MA
Sherman
Bryan W
BW
True
Timothy
T
Cowan
Conrad
C
D000318:Adrenergic beta-Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D001831:Body Temperature / Q000187:drug effects; D016466:CHO Cells; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D000242:Cyclic AMP / Q000096:biosynthesis; D004285:Dogs; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D011869:Radioligand Assay; D022702:Receptors, Adrenergic, beta-3 / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013453:Sulfonylurea Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013817:Thermography; D000096926:Benzenesulfonamides
D000318:Adrenergic beta-Agonists; D000814:Aniline Compounds; D000242:Cyclic AMP; D022702:Receptors, Adrenergic, beta-3; D013449:Sulfonamides; D013453:Sulfonylurea Compounds; C446944:N-((3-((2-((2-hydroxy-2-(3-chlorophenyl)ethyl)amino)propyl)amino)phenyl)acetyl)-4-methylbenzenesulfonamide; D000096926:Benzenesulfonamides; C446943:N-((4-((2-((2-hydroxy-2-(3-chlorophenyl)ethyl)amino)propyl)amino)phenyl)acetyl)-4-methylbenzenesulfonamide