Synthesis,Crystal Structure and URAT1 Inhibitory Activity of 2-((5-Bromo-4-((4-cyclobutylnaphth-1-yl)methyl)-4H-1,2,4-triazol-3-yl)thio)acetic Acid

【摘要】 The title compound 1 was prepared from 1-bromonaphthalene and cyclobutanone in 11 steps, and its structure was determined by single-crystal X-ray diffraction for its monohydrate. The title compound 1 crystallizes as its monohydrate(C₁₉H₁₈BrN₃O₂S·H₂O, M_r = 450.35) in triclinic, space group P1 with a = 8.195（3）, b = 8.703（3）, c = 14.610（4） ?, α = 90.290（4）, β = 93.764（9）, γ = 116.435（10）°, V = 930.3（5） ?³, Z = 2, D_c = 1.608 g/cm³, F（000） = 460, μ = 2.347 mm^-1, the final R = 0.0314 and wR = 0.0746 for 3368 observed reflections（I > 2σ（I））. The cyclobutane ring adopts a puckered conformation. The crystal lattice is stabilized by three intermolecular hydrogen bonds involving the existing water molecule. 1 was a highly active urate transporter 1（URAT1） inhibitor as it was 14-fold more active in in vitro human URAT1 inhibitory assay versus positive control lesinurad(IC₅₀ = 0.51 μM for 1 vs. 7.18 μM for lesinurad against human URAT1). The single-crystal structure for the monohydrate of 1 reported herein represents the first unambiguous structural determination of a novel flexible molecular scaffold we discovered earlier that was very promising for the design of highly active URAT1 inhibitors.更多还原

【Abstract】 The title compound 1 was prepared from 1-bromonaphthalene and cyclobutanone in 11 steps, and its structure was determined by single-crystal X-ray diffraction for its monohydrate. The title compound 1 crystallizes as its monohydrate(C₁₉H₁₈BrN₃O₂S·H₂O, M_r = 450.35) in triclinic, space group P1 with a = 8.195（3）, b = 8.703（3）, c = 14.610（4） ?, α = 90.290（4）, β = 93.764（9）, γ = 116.435（10）°, V = 930.3（5） ?³, Z = 2, D_c = 1.608 g/cm³, F（000） = 460, μ = 2.347 mm^-1, the final R = 0.0314 and wR = 0.0746 for 3368 observed reflections（I > 2σ（I））. The cyclobutane ring adopts a puckered conformation. The crystal lattice is stabilized by three intermolecular hydrogen bonds involving the existing water molecule. 1 was a highly active urate transporter 1（URAT1） inhibitor as it was 14-fold more active in in vitro human URAT1 inhibitory assay versus positive control lesinurad(IC₅₀ = 0.51 μM for 1 vs. 7.18 μM for lesinurad against human URAT1). The single-crystal structure for the monohydrate of 1 reported herein represents the first unambiguous structural determination of a novel flexible molecular scaffold we discovered earlier that was very promising for the design of highly active URAT1 inhibitors.更多还原