Discovery of Novel Indazole Derivatives as Highly Potent and Selective Human β₃‑Adrenergic Receptor Agonists with the Possibility of Having No Cardiovascular Side Effects

Novel indazole derivatives were prepared and evaluated for their biological activity and cardiovascular safety profile as human β₃-adrenergic receptor (AR) agonists. Although the initial hit compound 5 exhibited significant β₃-AR agonistic activity (EC₅₀ = 21 nM), it also exhibited agonistic activity at the α_1A-AR (EC₅₀ = 219 nM, selectivity: α_1A/β₃ = 10-fold). The major metabolite of 5, which was an oxidative product at the indazole 3-methyl moiety, gave a clue to a strategy for improvement of the selectivity for β₃-AR agonistic activity versus α_1A-AR agonistic activity. Thus, modification of the 3-substituent of the indazole moiety effectively improved the selectivity to develop compound 11 with potent β₃-AR agonistic activity (EC₅₀ = 13 nM) and high selectivity (α_1A/β₃ = >769-fold). Compound 11 was also inactive toward β₁ and β₂-ARs and showed dose dependent β₃-AR mediated relaxation of marmoset urinary bladder smooth muscle, while it did not obviously affect heart rate or blood pressure (iv, 3 mg/kg) in anesthetized rats.