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 i...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, Mr = 450.35） in triclinic, space group P1 with a = 8.195（3）, b = 8.703（3）, c = 14.610（4） A, α = 90.290（4）, β = 93.764（9）, γ = 116.435（10）°, V = 930.3（5）A^3, Z = 2, Dc = 1.608 g/cm^3, 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.展开更多
Gout is caused by the deposition of uric acid as monosodium urate（MSU）. Chronic hyperuricemia is the necessary condition for MSU deposition, which arises from over-production and/or under-excretion of uric acid. Ren...Gout is caused by the deposition of uric acid as monosodium urate（MSU）. Chronic hyperuricemia is the necessary condition for MSU deposition, which arises from over-production and/or under-excretion of uric acid. Renal under-excretion of uric acid accounts for greater than 90% of the patients with hyperuricemia, making URAT1 inhibitors, which act through uricosuric effect a promising class of urate-lowering therapy（ULT）. This review aims at the summary and discussion of the latest development of URAT1 inhibitors for the treatment of hyperuricemia and gout and providing an insight into their structure-activity relationship（SAR）, which will be helpful to the design of URAT1 inhibitors for both academic research and pharmaceutical industry. The current development pipeline of URAT1 inhibitors is promising and encouraging.展开更多
Systematic structure-activity relationship（SAR） exploration of a moderately active tetrazole-bearmg lesinurad-based hit If led to the discovery of a potent uric acid transporter I（URAT1） inhibitor li, which posses...Systematic structure-activity relationship（SAR） exploration of a moderately active tetrazole-bearmg lesinurad-based hit If led to the discovery of a potent uric acid transporter I（URAT1） inhibitor li, which possessed a novel molecular skeleton and was 11-fold more potent than the parent lesinurad against human URAT1 in-vitro （IC50=0.66 gmol/L for li vs. 7.18 μmol/L for lesinurad）.展开更多
基金Supported by the Key Projects of Tianjin Science and Technology Support Plan(16YFZCSY00910)Tianjin Natural Science Foundation(12JCYBJC18800 and 13JCQNJC13700)Shandong Natural Science Foundation(ZR2015BM028)
文摘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, Mr = 450.35） in triclinic, space group P1 with a = 8.195（3）, b = 8.703（3）, c = 14.610（4） A, α = 90.290（4）, β = 93.764（9）, γ = 116.435（10）°, V = 930.3（5）A^3, Z = 2, Dc = 1.608 g/cm^3, 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.
基金Supported by Key Projects of Tianjin Science and Technology Support Plan(16YFZCSY00910)Natural Science Foundation of Shandong Province(ZR2015BM028)
文摘Gout is caused by the deposition of uric acid as monosodium urate（MSU）. Chronic hyperuricemia is the necessary condition for MSU deposition, which arises from over-production and/or under-excretion of uric acid. Renal under-excretion of uric acid accounts for greater than 90% of the patients with hyperuricemia, making URAT1 inhibitors, which act through uricosuric effect a promising class of urate-lowering therapy（ULT）. This review aims at the summary and discussion of the latest development of URAT1 inhibitors for the treatment of hyperuricemia and gout and providing an insight into their structure-activity relationship（SAR）, which will be helpful to the design of URAT1 inhibitors for both academic research and pharmaceutical industry. The current development pipeline of URAT1 inhibitors is promising and encouraging.
基金Supported by the Key Projects of Tianjin Science and Technology Support Plan, China（No. 16YFZC SY00910） and the Natu- ral Science Foundation of Shandong Province, China（No.ZR2015BM028）.
文摘Systematic structure-activity relationship（SAR） exploration of a moderately active tetrazole-bearmg lesinurad-based hit If led to the discovery of a potent uric acid transporter I（URAT1） inhibitor li, which possessed a novel molecular skeleton and was 11-fold more potent than the parent lesinurad against human URAT1 in-vitro （IC50=0.66 gmol/L for li vs. 7.18 μmol/L for lesinurad）.
