title: Discovery of a potent, orally bioavailable beta(3) adrenergic receptor agonist, (R)-N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[4 -[4-(trifluoromethyl)phenyl]thiazol-2-yl]benzenesulfonamide.
abstract: As part of our investigation into the development of orally bioavailable beta(3) adrenergic receptor agonists, we have identified a series of pyridylethanolamine analogues possessing a substituted thiazole benzenesulfonamide pharmacophore that are potent human beta(3) agonists with excellent selectivity against other human beta receptor subtypes. Several of these compounds also exhibited an improved pharmacokinetic profile in dogs. For example, thiazole sulfonamide 2e (R = 4-F(3)C-C(6)H(4)) is a potent full beta(3) agonist (EC(50) = 3.6 nM, 94% activation) with >600-fold selectivity over the human beta(1) and beta(2) receptors, which also displays good oral bioavailability in several mammalian species, as well as an extended duration of action.
authors.affiliation: Merck Research Laboratories, Rahway, New Jersey 07065, USA. robert_mathvink@merck.com
authors.forename: R J
authors.initials: RJ
authors.lastname: Mathvink
authors.forename: J S
authors.initials: JS
authors.lastname: Tolman
authors.forename: D
authors.initials: D
authors.lastname: Chitty
authors.forename: M R
authors.initials: MR
authors.lastname: Candelore
authors.forename: M A
authors.initials: MA
authors.lastname: Cascieri
authors.forename: L F
authors.initials: LF
authors.lastname: Colwell
authors.forename: L
authors.initials: L
authors.lastname: Deng
authors.forename: W P
authors.initials: WP
authors.lastname: Feeney
authors.forename: M J
authors.initials: MJ
authors.lastname: Forrest
authors.forename: G J
authors.initials: GJ
authors.lastname: Hom
authors.forename: D E
authors.initials: DE
authors.lastname: MacIntyre
authors.forename: R R
authors.initials: RR
authors.lastname: Miller
authors.forename: R A
authors.initials: RA
authors.lastname: Stearns
authors.forename: L
authors.initials: L
authors.lastname: Tota
authors.forename: M J
authors.initials: MJ
authors.lastname: Wyvratt
authors.forename: M H
authors.initials: MH
authors.lastname: Fisher
authors.forename: A E
authors.initials: AE
authors.lastname: Weber
mesh_terms: D000284:Administration, Oral; D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D016466:CHO Cells; D003001:Cloning, Molecular; D006224:Cricetinae; D004285:Dogs; D005990:Glycerol / Q000097:blood; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D011869:Radioligand Assay; D051381:Rats; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D022702:Receptors, Adrenergic, beta-3 / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000096926:Benzenesulfonamides
chemical_list: D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists; D005990:Glycerol; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D022702:Receptors, Adrenergic, beta-3; D013449:Sulfonamides; D013844:Thiazoles; C415563:N-(4-(2-((2-hydroxy-2-(3-pyridinyl)ethyl)amino)ethyl)phenyl)-4-(4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)benzenesulfonamide; D000096926:Benzenesulfonamides