Biarylaniline phenethanolamines as potent and selective beta(3) adrenergic receptor agonists

• Published in: Journal of medicinal chemistry Vol. 49; no. 9; pp. 2758 - 2771
• Main Authors: Uehling, DE, Shearer, BG, Donaldson, KH, Chao, EY, Deaton, DN, Adkison, KK, Brown, KK, Cariello, NF, Faison, WL, Lancaster, ME, Lin, J, Hart, R, Milliken, TO, Paulik, MA, Sherman, BW, Sugg, EE, Cowan, C
• Format: Journal Article
• Language: English
• Published: WASHINGTON Amer Chemical Soc 04.05.2006
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; DETRUSOR; ENERGY-EXPENDITURE; BROMINATION; RECEPTOR AGONISTS; BETA-ADRENOCEPTOR; RELAXATION; L-796568; BACTERIAL MUTAGENICITY; DISCOVERY
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0509445

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, 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, 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.