title: Biarylaniline phenethanolamines as potent and selective beta3 adrenergic receptor agonists.
abstract: The synthesis of a series of phenethanolamine aniline agonists that contain an aniline ring on the right-hand side of the molecule substituted at the meta position with a benzoic acid or a pyridyl carboxylate is described. Several of the analogues (e.g., 34, 36-38, 40, and 44) have high beta(3) adrenergic receptor (AR) potency and selectivity against beta(1) and beta(2) ARs in Chinese hamster ovary (CHO) cells expressing beta ARs. The dog pharmacokinetic profile of some of these analogues showed >25% oral bioavailability and po half-lives of at least 1.5 h. Among the compounds described herein, the 3,3'-biarylaniline carboxylate derivatives 36, 38 and the phenylpyridyl derivative 44 demonstrated outstanding in vitro properties and reasonable dog pharmacokinetic profiles. These three analogues also showed dose dependent beta(3) AR mediated responses in mice. The ease of synthesis and superior dog pharmacokinetics of compound 38 relative to that of 44 in combination with its in vitro profile led us to choose this compound as a development candidate for the treatment of type 2 diabetes.
authors.affiliation: Department of Medicinal Chemistry, GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA. david.e.uehling@gsk.com
authors.forename: David E
authors.initials: DE
authors.lastname: Uehling
authors.forename: Barry G
authors.initials: BG
authors.lastname: Shearer
authors.forename: Kelly H
authors.initials: KH
authors.lastname: Donaldson
authors.forename: Esther Y
authors.initials: EY
authors.lastname: Chao
authors.forename: David N
authors.initials: DN
authors.lastname: Deaton
authors.forename: Kim K
authors.initials: KK
authors.lastname: Adkison
authors.forename: Kathleen K
authors.initials: KK
authors.lastname: Brown
authors.forename: Neal F
authors.initials: NF
authors.lastname: Cariello
authors.forename: Walter L
authors.initials: WL
authors.lastname: Faison
authors.forename: Mary E
authors.initials: ME
authors.lastname: Lancaster
authors.forename: Jasmine
authors.initials: J
authors.lastname: Lin
authors.forename: Robert
authors.initials: R
authors.lastname: Hart
authors.forename: Tula O
authors.initials: TO
authors.lastname: Milliken
authors.forename: Mark A
authors.initials: MA
authors.lastname: Paulik
authors.forename: Bryan W
authors.initials: BW
authors.lastname: Sherman
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Sugg
authors.forename: Conrad
authors.initials: C
authors.lastname: Cowan
mesh_terms: D058667:Adrenergic beta-3 Receptor Agonists; D000814:Aniline Compounds / Q000737:chemistry*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002460:Cell Line; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D004285:Dogs; D019856:Ethanolamine / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006031:Glycosylation / Q000187:drug effects; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D015394:Molecular Structure; D022702:Receptors, Adrenergic, beta-3 / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D058667:Adrenergic beta-3 Receptor Agonists; D000814:Aniline Compounds; D001786:Blood Glucose; D006454:Hemoglobins; D022702:Receptors, Adrenergic, beta-3; D019856:Ethanolamine; D000242:Cyclic AMP; C023650:aniline