Discovery of Novel Indazole Derivatives as Orally Available β₃‑Adrenergic Receptor Agonists Lacking Off-Target-Based Cardiovascular Side Effects

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 α1A-AR (β1/β3, β2/β3, and α1A/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 (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 β3-AR agonist, which may serve as a candidate drug for the treatment
of overactive bladder without off-target-based cardiovascular side
effects.