Thermal and Photochemical Isomerization of Tetraaryl Tetrakis(trifluoromethyl)[4]radialenes

The isomerization of tetraaryl tetrakis(trifluoromethyl)[4]radialenes was studied. When type II (all-Z) isomers of 5,6,7,8-tetraaryl-5,6,7,8-tetrakis(trifluoromethyl)[4]radialenes were heated in tetralin at 170−200 °C, isomerization occurred to give mixtures of four [4]radialenes in a ratio of ca. I:II:III:IV = 1:10:5:1. However, when the isomeric mixtures were heated in the solid state at the same temperature, selective isomerization took place to give type II isomers in good selectivity (>91%). Upon irradiation with light, the type II isomers first isomerized to mixtures of the four [4]radialene isomers (I:II:III:IV = 2:2:48:48) and then rearranged to cyclobuta[b]naphthalenes via a 6π-electrocyclic reaction followed by 1,3-hydrogen migration

Thermal and Photochemical Isomerization of Tetraaryl Tetrakis(trifluoromethyl)[4]radialenes

The isomerization of tetraaryl tetrakis(trifluoromethyl)[4]radialenes was studied. When type II (all-Z) isomers of 5,6,7,8-tetraaryl-5,6,7,8-tetrakis(trifluoromethyl)[4]radialenes were heated in tetralin at 170−200 °C, isomerization occurred to give mixtures of four [4]radialenes in a ratio of ca. I:II:III:IV = 1:10:5:1. However, when the isomeric mixtures were heated in the solid state at the same temperature, selective isomerization took place to give type II isomers in good selectivity (>91%). Upon irradiation with light, the type II isomers first isomerized to mixtures of the four [4]radialene isomers (I:II:III:IV = 2:2:48:48) and then rearranged to cyclobuta[b]naphthalenes via a 6π-electrocyclic reaction followed by 1,3-hydrogen migration

Thermal and Photochemical Isomerization of Tetraaryl Tetrakis(trifluoromethyl)[4]radialenes

The isomerization of tetraaryl tetrakis(trifluoromethyl)[4]radialenes was studied. When type II (all-Z) isomers of 5,6,7,8-tetraaryl-5,6,7,8-tetrakis(trifluoromethyl)[4]radialenes were heated in tetralin at 170−200 °C, isomerization occurred to give mixtures of four [4]radialenes in a ratio of ca. I:II:III:IV = 1:10:5:1. However, when the isomeric mixtures were heated in the solid state at the same temperature, selective isomerization took place to give type II isomers in good selectivity (>91%). Upon irradiation with light, the type II isomers first isomerized to mixtures of the four [4]radialene isomers (I:II:III:IV = 2:2:48:48) and then rearranged to cyclobuta[b]naphthalenes via a 6π-electrocyclic reaction followed by 1,3-hydrogen migration

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 <b>5</b> 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 <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 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 <b>11</b> with potent β₃-AR agonistic activity (EC₅₀ = 13 nM) and high selectivity (α_1A/β₃ = >769-fold). Compound <b>11</b> 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

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 <b>5</b> 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 <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 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 <b>11</b> with potent β₃-AR agonistic activity (EC₅₀ = 13 nM) and high selectivity (α_1A/β₃ = >769-fold). Compound <b>11</b> 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

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 <b>8</b> 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 <b>15</b> 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 <b>15</b> showed dose-dependent β₃-AR-mediated responses in marmoset urinary bladder smooth muscle, had a desirable metabolic stability and pharmacokinetic profile (<i>C</i>_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 <b>15</b> 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