Potent, selective benzenesulfonamide agonists of the human beta 3 adrenergic receptor.
A cloned human beta 3 adrenergic receptor assay was used to identify phenoxypropanolamine agonist 1. SAR studies led to the identification of benzenesulfonamide derivative 20, a 6.3 nM beta 3 agonist which shows 30-fold selectivity for beta 3 agonist activity over beta 1 and beta 2 receptor binding. Further refinement of this lead provided 4-bromo derivative 39, a subnanomolar agonist with 660-fold and 230-fold selectivity over beta 1 and beta 2, respectively.
Weber
A E
AE
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, New Jersey 07065, USA.
Mathvink
R J
RJ
Perkins
L
L
Hutchins
J E
JE
Candelore
M R
MR
Tota
L
L
Strader
C D
CD
Wyvratt
M J
MJ
Fisher
M H
MH
D000318:Adrenergic beta-Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003001:Cloning, Molecular; D015195:Drug Design; D006801:Humans; D008968:Molecular Conformation; D015394:Molecular Structure; D011412:Propanolamines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000502:physiology; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects; D022702:Receptors, Adrenergic, beta-3; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D000096926:Benzenesulfonamides
D000318:Adrenergic beta-Agonists; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D022702:Receptors, Adrenergic, beta-3; D011994:Recombinant Proteins; D013449:Sulfonamides; D000096926:Benzenesulfonamides; C033394:CGP 12177