| Hyperuricemia and gout are pathological conditions characterized by overproduction or under-excretion of uric acid,a product of purine catabolism physiologically excreted in the urine.Both conditions are associated with chronic diseases such as hypertension,diabetes mellitus,metabolic syndrome,renal and cardiovascular diseases.The most common clinical features of hyperuricemia are accompanied by crystallization and deposition of uric acid in joints and surrounding tissues,however the precise mechanism for uric acid-induced tissue injury remains unclear.Lesinuard is a new drug used for the treatment of gout.It was discovered fortuitously by Ardea Biosciences in 2008.Lesinurad was approved on 22th Dec 2015 by US FDA,and was noted to increase the excretion of uric acid by inhibiting the uric acid salt transport protein 1(URAT1).URAT1 is considered to be the main protein existing in kidney used to transport the uric acid salt,which is able to transfer the uric acid from the lumen proximal to tubule epithelial cells and translate into single carboxylic acid salt.In clinical trials,lesinuard has been well tolerated with dose-dependent reductions in serum uric acid.Moreover,co-administration of xanthine oxidase inhibitors and lesinurad can safely accelerate urate reduction in gout patients.However,lesinurad is very expensive and it is only listed in the US and Europe.So,we need to find a more efficient,economical synthetic route for industrial production before the patent expires.In this thesis,based on the several kinds of synthetic methods reported by different patents,we disclosed an optimized synthetic route of lesinurad,which has great potential for industrial production.In the first section of this thesis,we mainly focus on the synthetic route optimization of lesinurad to improve the total yield and shorten the reaction steps.4-Bromonaphthalen-l-amine was choosed as the starting material,4-cyclopropylnaphthalen-l-amine was obtained through Suzuki coupling reaction.Then 1,1'-ThiocarbonylDiimidazole was used to afford the key intermediate 1-cyclopropyl-4-isothiocyanatonaphthalene instead of thiophosgene.Finally,lesinurad was prepared after alkylation,bromination and hydrolization.In general,the improved process shortened reaction steps and increased the total yield from 9.5%to 38.8%.In addition,the stability and repeatability of the synthetic route was ensured by a three-batches-test,prviding an important approach for the industrial production.Lesinurad as the pioneering drug,has a larger space for structural optimization.Compared with pioneering innovative drug development,seeking me-too drugs is a less difficult and risky but more successful way,and is regarded as an important and practical approach in drug research.Therefore,to find Lesinurad me-too drugs,based on analyzing the pharmacophore features of lesinurad,the second section of this thesis is to design and synthesize a series of URAT1 derivatives utilizing the scaffold hopping strategy.We focused on the triazole moiety and thioglycolic chain and synthesized 40 compounds with modifications in these regions.All newly synthesized target compounds were primarily evaluated for their activities of reducing blood uric acid in vivo(mice).The results showed that most of the novel compounds exhibited high potency in reducing blood uric acid.Among them,19 promising compounds displayed higher activity than lesinurad.The URAT1 inhibition assay was performed as well,and some compounds exhibited more favorable URAT1 inhibition potency than lesinurad.Among them,the IC50 of compound T7 was 1.175 mol/L,which was 5.6 times higher than the positive control Lesinurad(IC50=6.597 mol/L),indicating that the newly designed compounds have great potential to be further developed as novel anti-gout agents. |
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