Biarylaniline phenethanolamines as potent and selective beta3 adrenergic receptor agonists.
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.
Uehling
David E
DE
Department of Medicinal Chemistry, GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA. david.e.uehling@gsk.com
Shearer
Barry G
BG
Donaldson
Kelly H
KH
Chao
Esther Y
EY
Deaton
David N
DN
Adkison
Kim K
KK
Brown
Kathleen K
KK
Cariello
Neal F
NF
Faison
Walter L
WL
Lancaster
Mary E
ME
Lin
Jasmine
J
Hart
Robert
R
Milliken
Tula O
TO
Paulik
Mark A
MA
Sherman
Bryan W
BW
Sugg
Elizabeth E
EE
Cowan
Conrad
C
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
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