| Gout is the most common inflammatory arthritis,which is caused by the deposition of monosodium urate(MSU)in articular and periarticular tissues.Gout is one of the oldest diseases recognized by physicians.The prevalence of gout and hyperuricemia has been on the rise over the past few decades,presenting a significant burden on the individual and community.Acute gout attack was often treated with colchicine,nonsteroidal antiinflammatory drugs(NSAIDs),corticosteroids and so on.However,the aim of treatment of gout is dissolution of MSU crystals by urate-lowering therapy(ULT)with xanthine oxidase inhibitors(XOIs)such as allopurinol and febuxostat,uricosuric drugs such as probenecid,sulfinpyrazone and benzbromarone,and uricase such as pegloticase.However,the XOIs are often associated with low patient response rates;most URAT1 inhibitors are associated with a variety of severe side effects or drawbacks,such as severe hepatotoxicity of benzbromarone and drug interactions of probenecid with a lot of other drugs.Besides,some of them are not available in specific countries.XOIs are usually used as first-line ULT,and when patients are refractory to or contraindicated for XOIs,uricosuric drugs can be used as second-line therapy.Uricase are only indicated for patients with severe gout such as those with tophaceous deformities and complications.A third of urate is excreted via the gastrointestinal tract,and two-thirds via kidney.Most of the urate filtered by the kidney is reabsorbed,and this process is mainly mediated by uric acid transporter 1(URAT1)which,also known as urate-anion exchanger 1,is prominent in epithelial cells of proximal tubules in the renal cortex.Given the fact that 90%of the patients with hyperuricemia are urate under-excretors,URAT1 inhibitors,which lower sUA by inducing uricosuria,were believed to be a very promising class of uricosuric agents for the treatment of hyperuricemia and gout.Lesinurad,a novel URAT1 inhibitor which was approved by FDA in December 2015 was derived.In vitro activity of these derivatives was tested and compared with lesinurad in order to find a potential URAT1 inhibitors which bio-activity close to or even better than lesinurad.The present thesis describes the drug discovery of highly potent URAT1 inhibitors using lesinurad as structural template.During the study of lesinurad derivatives in an earlier investigation in our laboratories,we were surprised to discover a significantly active URAT1 inhibitor III-lc,the sodium salt of III-llc,which bears a CH2 moiety inserted between the triazole and naphthalene rings in the molecule of lesinurad and was 31-fold more active than parent lesinurad(IC50=0.231μM for III-lc against human URAT1 vs 7.18μM for lesinurad).Encouraged by this promising preliminary finding,we carried out a systematic structure-activity relationship(SAR)exploration of this novel molecular skeleton with expectation of a better understanding of the SAR of this more flexible molecular skeleton as compared to the more rigid one of lesinurad,which includes the modification of the halogen atom at the 5-position of the 1,2,4-triazole ring,the substituents at the a-position of the carboxylate,the substituents at the 4-position of naphthalene ring and lengths of two linkers,i.e.the two CH2 linkers connecting the triazole ring and naphthalene ring as well as the triazole ring and the carboxylate,respectively.Fortunately,the systematic SAR led to the discovery of Ⅲ-1j and Ⅲ-1m as highly active URAT1 inhibitors,which were 78-and 76-fold more active than parent lesinurad in in vitro URAT1 inhibitory assay,respectively(IC50 values for Ⅲ-1j and Ⅲ-1m were 0.092μM and 0.094μM,respectively,against human URAT1 vs 7.18 μM for lesinurad).In addition,the SAR exploration identified flexible naphthyltriazolylmethane as a novel molecular skeleton that will be valuable for the design of URAT1 inhibitors as compared with the rigid naphthyltriazole skeleton presented in lesinurad.During this process,we studied the single-crystal structure of 2-((5-bromo-4-((4-cyclobutylnaphth-1-yl)methyl)-4H-1,2,4-triazol-3-yl)thio)acetic acid as its monohydrate,further confirming the unambiguous structure of this novel molecular skeleton。1-Substituted cyclopropanecarboxylates represent an interesting class of compounds in both synthetic organic chemistry and medicinal chemistry.In the above effort of discovering novel URAT1 inhibitors for the treatment of hyperuricemia associated with gout in our laboratories,compound Ⅳ-2 with a moiety of 1-thiocyclopropanecarboxylate was needed.An initial attempt to synthesize Ⅳ-2 by a seemingly straightforward approach involving the substitution reaction of thioneⅣ-12k and ethyl 1-bromocyclopropanecarboxylate Ⅳ-3b failed because no reaction occurred even in refluxing DMF.Literatures for the synthesis of 1-thiocyclopropanecarboxylate moiety either lack substrate generality or experimentally irreproducible in our laboratories.We developed a facile synthetic approach to 1-thiocyclopropanecarboxylates based on that for 1-oxycyclopropanecarboxylates after systematic optimizations of the reaction conditions and intensive exploration of substrate scope;during the process,we devised another novel synthetic approach that is complementary to the first one.The two approaches are complementary in many respects,allowing for flexible choices according to specific requirements for the characteristics of synthetic methods. |
