Discovery of Novel Indazole Derivatives as Orally Available β 3 -Adrenergic Receptor Agonists Lacking Off-Target-Based Cardiovascular Side Effects.

We previously discovered that indazole derivative 8 was a highly selective beta(3)-adrenergic receptor (beta(3)-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 beta(3)-AR agonist (EC50 = 18 nM) being inactive to beta(1)-, beta(2)-, and alpha(1A)-AR (beta(1)/beta(3), beta(2)/beta(3), and alpha(1A)/beta(3) > 556-fold). Compound 15 showed dose-dependent beta(3)-AR-mediated responses in marmoset urinary bladder smooth muscle, had a desirable metabolic stability and pharmacokinetic profile (Cmax 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 beta(3)-AR agonist, which may serve as a candidate drug for the treatment of overactive bladder without off-target-based cardiovascular side effects.