Discovery of Novel Indazole Derivatives as Orally Available β₃-Adrenergic Receptor Agonists Lacking Off-Target-Based...

We previously discovered that indazole derivative 8 was a highly selective β₃-adrenergic receptor (β₃-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 β₃-AR agonist (EC₅₀ = 18 nM) being inactive to β₁-, β₂-, and α_1A-AR (β₁/β₃, β₂/β₃, and α_1A/β₃ > 556-fold). Compound 15 showed dose-dependent β₃-AR-mediated responses in marmoset urinary bladder smooth muscle, had a desirable metabolic stability and pharmacokinetic profile (C_max 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 β₃-AR agonist, which may serve as a candidate drug for the treatment of overactive bladder without off-target-based cardiovascular side effects.