Uehling David E, Shearer Barry G, Donaldson Kelly H, Chao Esther Y, Deaton David N, Adkison Kim K, Brown Kathleen K, Cariello Neal F, Faison Walter L, Lancaster Mary E, Lin Jasmine, Hart Robert, Milliken Tula O, Paulik Mark A, Sherman Bryan W, Sugg Elizabeth E, Cowan Conrad
Department of Medicinal Chemistry, GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA.
J Med Chem. 2006 May 4;49(9):2758-71. 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 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.
描述了一系列苯乙醇胺苯胺激动剂的合成，这些激动剂在分子右侧的苯胺环上，间位被苯甲酸或吡啶羧酸酯取代。几种类似物（如34、36 - 38、40和44）在中国仓鼠卵巢（CHO）细胞中表达β肾上腺素能受体（AR）时，对β₃肾上腺素能受体具有高活性和对β₁和β₂肾上腺素能受体的选择性。其中一些类似物在犬体内的药代动力学特征显示口服生物利用度>25%，口服半衰期至少为1.5小时。在本文所述的化合物中，3,3'-联芳基苯胺羧酸酯衍生物36、38和苯基吡啶衍生物44表现出优异的体外性质和合理的犬药代动力学特征。这三种类似物在小鼠中也显示出剂量依赖性的β₃肾上腺素能受体介导的反应。化合物38相对于44易于合成且具有更优的犬药代动力学，结合其体外特征，使我们选择该化合物作为治疗2型糖尿病的开发候选药物。
