Wada Yasuhiro, Nakano Seiji, Morimoto Akifumi, Kasahara Ken-Ichi, Hayashi Takahiko, Takada Yoshio, Suzuki Hiroko, Niwa-Sakai Michiko, Ohashi Shigeki, Mori Mutsuhiro, Hirokawa Takatsugu, Shuto Satoshi
Pharmaceutical Research Center, Asahi Kasei Pharma Corporation , 632-1, Mifuku, Izunokuni, Shizuoka 410-2321, Japan.
Molecular Profiling Research Center for Drug Discovery (molprof), National Institute of Advanced Industrial Science and Technology (AIST) , 2-4-7 Aomi, Koto-ku, Tokyo 135-0064, Japan.
J Med Chem. 2017 Apr 27;60(8):3252-3265. doi: 10.1021/acs.jmedchem.6b01197. Epub 2017 Apr 11.
We previously discovered that indazole derivative 8 was a highly selective β-adrenergic receptor (β-AR) agonist, but it appeared to be metabolically unstable. To improve metabolic stability, further optimization of this scaffold was carried out. We focused on the sulfonamide moiety of this scaffold, which resulted in the discovery of compound 15 as a highly potent β-AR agonist (EC = 18 nM) being inactive to β-, β-, and α-AR (β/β, β/β, and α/β > 556-fold). Compound 15 showed dose-dependent β-AR-mediated responses in marmoset urinary bladder smooth muscle, had a desirable metabolic stability and pharmacokinetic profile (C and AUC), and did not obviously affect heart rate or mean blood pressure when administered intravenously (3 mg/kg) to anesthetized rats. Thus, compound 15 is a highly potent, selective, and orally available β-AR agonist, which may serve as a candidate drug for the treatment of overactive bladder without off-target-based cardiovascular side effects.
我们之前发现吲唑衍生物8是一种高度选择性的β-肾上腺素能受体（β-AR）激动剂，但它似乎代谢不稳定。为了提高代谢稳定性，我们对该骨架进行了进一步优化。我们聚焦于该骨架的磺酰胺部分，这导致发现化合物15是一种高效的β-AR激动剂（EC = 18 nM），对β1-、β2-和α-AR无活性（β1/β2、β2/β1和α1/β2 > 556倍）。化合物15在狨猴膀胱平滑肌中表现出剂量依赖性的β-AR介导的反应，具有理想的代谢稳定性和药代动力学特征（Cmax和AUC），并且在对麻醉大鼠静脉注射（3 mg/kg）时对心率或平均血压没有明显影响。因此，化合物15是一种高效、选择性且口服可用的β-AR激动剂，可作为治疗膀胱过度活动症且无基于脱靶的心血管副作用的候选药物。
