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Discovery of Novel Indazole Derivatives as Highly Potent and Selective Human β<sub>3</sub>‑Adrenergic Receptor Agonists with the Possibility of Having No Cardiovascular Side Effects
Abstract
Novel indazole derivatives were prepared and evaluated for their biological activity and cardiovascular safety profile as human β<sub>3</sub>-adrenergic receptor (AR) agonists. Although the initial hit compound <b>5</b> exhibited significant β<sub>3</sub>-AR agonistic activity (EC<sub>50</sub> = 21 nM), it also exhibited agonistic activity at the α<sub>1A</sub>-AR (EC<sub>50</sub> = 219 nM, selectivity: α<sub>1A</sub>/β<sub>3</sub> = 10-fold). The major metabolite of <b>5</b>, which was an oxidative product at the indazole 3-methyl moiety, gave a clue to a strategy for improvement of the selectivity for β<sub>3</sub>-AR agonistic activity versus α<sub>1A</sub>-AR agonistic activity. Thus, modification of the 3-substituent of the indazole moiety effectively improved the selectivity to develop compound <b>11</b> with potent β<sub>3</sub>-AR agonistic activity (EC<sub>50</sub> = 13 nM) and high selectivity (α<sub>1A</sub>/β<sub>3</sub> = >769-fold). Compound <b>11</b> was also inactive toward β<sub>1</sub> and β<sub>2</sub>-ARs and showed dose dependent β<sub>3</sub>-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 ratsSimilar works
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