Biarylaniline Phenethanolamines as Potent and Selective β₃Adrenergic 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.

Pharmacological profile of β3-adrenoceptor agonists in clinical development for the treatment of overactive bladder syndrome

“…In the first series, the EC 50 of solabegron at human β 1 -, β 2 -, and β 3 -adrenoceptors was 1,259, 3,981, and 3.98 nM, respectively, as compared to 1.0, 0.16, and 3.16 nM, respectively, for isoprenaline, i.e., solabegron was 1,000-and 316-fold selective for β 3 -vs. β 1 -or β 2 -adrenoceptors (Uehling et al 2006); in these experiments, the efficacy of solabegron relative to isoprenaline was 0.79 at β 3 -adrenoceptors but 0.02 and 0.05 at β 1 -or β 2 -adrenoceptors, respectively. In a second series of experiments, solabegron stimulated cyclic AMP accumulation via human β 3 -adrenoceptors with an EC 50 of 6.9 nM as compared to 3.3 nM for isoprenaline, and the efficacy of solabegron relative to isoprenaline was 0.89 (Hicks et al 2007).…”

“…Thus, a 14-day oral treatment of db/db mice with solabegron dose-dependently lowered plasma glucose, HbA1c, and insulin levels and elicited a thermogenic response from the brown fat-rich interscapular region (Uehling et al 2006). Given the differential role of β 3 -adrenoceptors in glucose and lipid metabolism between rodents and humans (Arch 2008), the relevance of such findings for OAB patients is difficult to predict.…”

GW427353 (Solabegron), a Novel, Selective β3-Adrenergic Receptor Agonist, Evokes Bladder Relaxation and Increases Micturition Reflex Threshold in the Dog

“…Thus, selective ␤ 3 -AR stimulation of human bladder would be expected to cause bladder relaxation, and as such it may represent a novel strategy in the treatment of overactive bladder. The present studies investigated the effects of a novel, selective ␤ 3 -AR agonist, GW427353 (solabegron; Uehling et al, 2006), on bladder function in the dog using in vitro and in vivo techniques.…”

Dose-response effect of a β3-adrenergic receptor agonist, solabegron, on gastrointestinal transit, bowel function, and somatostatin levels in health

“…Solabegron hydrochloride is a potent and selective in vitro agonist of human ␤ 3-AR activity compared with human ␤1-and ␤2-adrenergic activity and is not an antagonist at either ␤1-or ␤2-ARs. Solabegron is a biaryl phenethanolamine compound [(1,1Ј-biphenyl)-3-carboxylic acid, 3Ј-((2-(((2R)-2-(3-chlorophenyl)-2-hydroxyethyl)amino)ethyl)amino)-, hydrochloride] of the class described by Uehling et al (27). The primary metabolite of solabegron is the O-acyl glucuronide metabolite solabegron; it has similar activity to solabegron as a selective ␤ 3-adrenergic agonist.…”