CDER167, a dual inhibitor of URAT1 and GLUT9, is a novel and potent uricosuric candidate for the treatment of hyperuricemia.
Humans
Cells, Cultured
Dose-Response Relationship, Drug
Glucose Transport Proteins, Facilitative
/ antagonists & inhibitors
HEK293 Cells
Hyperuricemia
/ drug therapy
Molecular Structure
Organic Anion Transporters
/ antagonists & inhibitors
Organic Cation Transport Proteins
/ antagonists & inhibitors
RNA, Messenger
/ antagonists & inhibitors
Structure-Activity Relationship
CDER167
RDEA3710
glucose transporter 9 (GLUT9)
gout
hyperuricemia
urate transporter 1 (URAT1)
uric acid-lowering drugs
Journal
Acta pharmacologica Sinica
ISSN: 1745-7254
Titre abrégé: Acta Pharmacol Sin
Pays: United States
ID NLM: 100956087
Informations de publication
Date de publication:
Jan 2022
Jan 2022
Historique:
received:
17
11
2020
accepted:
05
03
2021
pubmed:
27
3
2021
medline:
19
3
2022
entrez:
26
3
2021
Statut:
ppublish
Résumé
Urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) are important targets for the development of uric acid-lowering drugs. We previously showed that the flexible linkers of URAT1 inhibitors could enhance their potency. In this study we designed and synthesized CDER167, a novel RDEA3710 analogue, by introducing a linker (methylene) between the naphthalene and pyridine rings to increase flexibility, and characterized its pharmacological and pharmacokinetics properties in vitro and in vivo. We showed that CDER167 exerted dual-target inhibitory effects on both URAT1 and GLUT9: CDER167 concentration-dependently inhibited the uptake of [
Identifiants
pubmed: 33767379
doi: 10.1038/s41401-021-00640-5
pii: 10.1038/s41401-021-00640-5
pmc: PMC8724292
doi:
Substances chimiques
Glucose Transport Proteins, Facilitative
0
Organic Anion Transporters
0
Organic Cation Transport Proteins
0
RNA, Messenger
0
SLC22A12 protein, human
0
SLC2A9 protein, human
0
CDER167
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
121-132Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2021. The Author(s), under exclusive licence to CPS and SIMM.
Références
Dalbeth N, Merriman TR, Stamp LK. Gout. Lancet. 2016;388:2039–52.
pubmed: 27112094
doi: 10.1016/S0140-6736(16)00346-9
Dalbeth N, Phipps-Green A, House ME, Gamble GD, Horne A, Stamp LK, et al. Body mass index modulates the relationship of sugar-sweetened beverage intake with serum urate concentrations and gout. Arthritis Res Ther. 2015;17:263.
pubmed: 26391224
pmcid: 4578754
doi: 10.1186/s13075-015-0781-4
Wu J, Zhang YP, Qu Y, Jie LG, Deng JX, Yu QH. Efficacy of uric acid-lowering therapy on hypercholesterolemia and hypertriglyceridemia in gouty patients. Int J Rheum Dis. 2019;22:1445–51.
pubmed: 31317680
doi: 10.1007/s00296-019-04342-4
Hou YL, Yang XL, Wang CX, Zhi LX, Yang MJ, You CG. Hypertriglyceridemia and hyperuricemia: a retrospective study of urban residents. Lipids Health Dis. 2019;18:81.
pubmed: 30935401
pmcid: 6444567
doi: 10.1186/s12944-019-1031-6
Wang Y, Chi J, Che K, Chen Y, Sun X, Wang Y, et al. Fasting plasma glucose and serum uric acid levels in a general Chinese population with normal glucose tolerance: a U-shaped curve. PLoS ONE. 2017;12:e180111.
Huffman JE, Albrecht E, Teumer A, Mangino M, Kapur K, Johnson T, et al. Modulation of genetic associations with serum urate levels by body-mass-index in humans. PLoS ONE. 2015;10:e119752.
doi: 10.1371/journal.pone.0119752
Kanbay M, Jensen T, Solak Y, Le M, Roncal-Jimenez C, Rivard C, et al. Uric acid in metabolic syndrome: from an innocent bystander to a central player. Eur J Intern Med. 2016;29:3–8.
pubmed: 26703429
doi: 10.1016/j.ejim.2015.11.026
So A, Thorens B. Uric acid transport and disease. J Clin Invest. 2010;120:1791–9.
pubmed: 20516647
pmcid: 2877959
doi: 10.1172/JCI42344
Strilchuk L, Fogacci F, Cicero AF. Safety and tolerability of available urate-lowering drugs: a critical review. Expert Opin Drug Saf. 2019;18:261–71.
pubmed: 30915866
doi: 10.1080/14740338.2019.1594771
Miner JN, Tan PK, Hyndman D, Liu S, Iverson C, Nanavati P, et al. Lesinurad, a novel, oral compound for gout, acts to decrease serum uric acid through inhibition of urate transporters in the kidney. Arthritis Res Ther. 2016;18:214.
pubmed: 27716403
pmcid: 5048659
doi: 10.1186/s13075-016-1107-x
Hautekeete ML, Henrion J, Naegels S, DeNeve A, Adler M, Deprez C, et al. Severe hepatotoxicity related to benzarone: a report of three cases with two fatalities. Liver. 1995;15:25–9.
pubmed: 7776854
doi: 10.1111/j.1600-0676.1995.tb00102.x
Gutman J, Kachur SP, Slutsker L, Nzila A, Mutabingwa T. Combination of probenecid-sulphadoxine-pyrimethamine for intermittent preventive treatment in pregnancy. Malar J. 2012;11:39.
pubmed: 22321288
pmcid: 3295670
doi: 10.1186/1475-2875-11-39
Robinson PC, Dalbeth N. Lesinurad for the treatment of hyperuricaemia in people with gout. Expert Opin Pharmacother. 2017;18:1875–81.
pubmed: 29103339
doi: 10.1080/14656566.2017.1401609
Shen Z, Gillen M, Miner JN, Bucci G, Wilson DM, Hall JW. Pharmacokinetics, pharmacodynamics, and tolerability of verinurad, a selective uric acid reabsorption inhibitor, in healthy adult male subjects. Drug Des Devel Ther. 2017;11:2077–86.
pubmed: 28744099
pmcid: 5511024
doi: 10.2147/DDDT.S140658
Wu T, Chen J, Dong S, Li H, Cao Y, Tian Y, et al. Identification and characterization of a potent and selective inhibitor of human urate transporter 1. Pharmacol Rep. 2017;69:1103–12.
pubmed: 28988709
doi: 10.1016/j.pharep.2017.04.022
Bibert S, Hess SK, Firsov D, Thorens B, Geering K, Horisberger JD, et al. Mouse GLUT9: evidences for a urate uniporter. Am J Physiol Ren Physiol. 2009;297:F612–9.
doi: 10.1152/ajprenal.00139.2009
Tian H, Liu W, Zhou Z, Shang Q, Liu Y, Xie Y, et al. Discovery of a flexible triazolylbutanoic acid as a highly potent uric acid transporter 1 (URAT1) Inhibitor. Molecules. 2016;21:1543.
pmcid: 6274368
doi: 10.3390/molecules21111543
Zhao T, Zhao Z, Lu F, Chang S, Zhang J, Pang J, et al. Two- and three-dimensional QSAR studies on hURAT1 inhibitors with flexible linkers: topomer CoMFA and HQSAR. Mol Divers. 2020;24:141–54.
pubmed: 30868332
doi: 10.1007/s11030-019-09936-5
Chen Y, Zhao Z, Li Y, Yang Y, Li L, Jiang Y, et al. Baicalein alleviates hyperuricemia by promoting uric acid excretion and inhibiting xanthine oxidase. Phytomedicine. 2020;80:153374.
pubmed: 33075645
doi: 10.1016/j.phymed.2020.153374
Chen Y, Zhao Z, Li Y, Li L, Jiang Y, Cao Y, et al. Characterizations of the urate transporter, GLUT9, and its potent inhibitors by patch-clamp technique. SLAS. Discovery. 2021;26:450–9.
Nakamura M, Fujita K, Toyoda Y, Nakamura M, Fujita K, Toyoda Y, et al. Investigation of the transport of xanthine dehydrogenase inhibitors by the urate transporter ABCG2. Drug Metab Pharmacokinet. 2018;33:77–81.
pubmed: 29342419
doi: 10.1016/j.dmpk.2017.11.002
Wu XH, Wang CZ, Wang SQ, Chao M, He Y, Zhang J, et al. Anti-hyperuricemia effects of allopurinol are improved by Smilax riparia, a traditional Chinese herbal medicine. J Ethnopharmacol. 2015;162:362–8.
pubmed: 25617746
doi: 10.1016/j.jep.2015.01.012
Sanguinetti MC, Jiang C, Curran ME, Keating MT. A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the I
pubmed: 7736582
doi: 10.1016/0092-8674(95)90340-2
Helliwell RM. Recording hERG potassium currents and assessing the effects of compounds using the whole-cell patch-clamp technique. Methods Mol Biol. 2008;491:279–95.
pubmed: 18998101
doi: 10.1007/978-1-59745-526-8_22
Kamiya K, Niwa R, Morishima M, Honjo H, Sanguinetti MC. Molecular determinants of hERG channel block by terfenadine and cisapride. J Pharm Sci. 2008;108:301–7.
doi: 10.1254/jphs.08102FP
Tan PK, Liu S, Gunic E, Miner JN. Discovery and characterization of verinurad, a potent and specific inhibitor of URAT1 for the treatment of hyperuricemia and gout. Sci Rep. 2017;7:665.
pubmed: 28386072
pmcid: 5429603
doi: 10.1038/s41598-017-00706-7
Gliozzi M, Malara N, Muscoli S, Mollace V. The treatment of hyperuricemia. Int J Cardiol. 2016;213:23–7.
pubmed: 26320372
doi: 10.1016/j.ijcard.2015.08.087
Taniguchi T, Ashizawa N, Matsumoto K, Saito R, Motoki K, Sakai M, et al. Pharmacological evaluation of dotinurad, a selective urate reabsorption inhibitor. J Pharmacol Exp Ther. 2019;371:162–70.
pubmed: 31371478
doi: 10.1124/jpet.119.259341
Tan PK, Ostertag TM, Miner JN. Mechanism of high affinity inhibition of the human urate transporter URAT1. Sci Rep. 2016;6:34995.
pubmed: 27713539
pmcid: 5054527
doi: 10.1038/srep34995
Woodward OM. ABCG2: the molecular mechanisms of urate secretion and gout. Am J Physiol Ren Physiol. 2015;309:F485–8.
doi: 10.1152/ajprenal.00242.2015
Miyata H, Takada T, Toyoda Y, Matsuo H, Ichida K, Suzuki H. Identification of febuxostat as a new strong ABCG2 inhibitor: potential applications and risks in clinical situations. Front Pharmacol. 2016;7:518.
pubmed: 28082903
pmcid: 5187494
doi: 10.3389/fphar.2016.00518
Qin Z, Wang S, Lin Y, Zhao Y, Yang S, Song J, et al. Antihyperuricemic effect of mangiferin aglycon derivative J99745 by inhibiting xanthine oxidase activity and urate transporter 1 expression in mice. Acta Pharm Sin B. 2018;8:306–15.
pubmed: 29719791
doi: 10.1016/j.apsb.2017.05.004
Chen M, Ye C, Zhu J, Zhang P, Jiang Y, Lu X, et al. Bergenin as a novel urate-lowering therapeutic strategy for hyperuricemia. Front Cell Dev Biol. 2020;8:703.
pubmed: 32850823
pmcid: 7403512
doi: 10.3389/fcell.2020.00703
Torralba KD, De Jesus E, Rachabattula S. The interplay between diet, urate transporters and the risk for gout and hyperuricemia: current and future directions. Int J Rheum Dis. 2012;15:499–506.
pubmed: 23253231
doi: 10.1111/1756-185X.12010
Kedar E, Simkin PA. A perspective on diet and gout. Adv Chronic Kidney Dis. 2012;19:392–7.
pubmed: 23089274
doi: 10.1053/j.ackd.2012.07.011
Mehmood A, Zhao L, Wang C, Nadeem M, Raza A, Ali N, et al. Management of hyperuricemia through dietary polyphenols as a natural medicament: a comprehensive review. Crit Rev Food Sci Nutr. 2019;59:1433–55.
pubmed: 29278921
doi: 10.1080/10408398.2017.1412939
Major TJ, Dalbeth N, Stahl EA, Merriman TR. An update on the genetics of hyperuricaemia and gout. Nat Rev Rheumatol. 2018;14:341–53.
pubmed: 29740155
doi: 10.1038/s41584-018-0004-x
Auberson M, Stadelmann S, Stoudmann C, Seuwen K, Koesters R, Thorens B, et al. SLC2A9 (GLUT9) mediates urate reabsorption in the mouse kidney. Pflug Arch. 2018;470:1739–51.
doi: 10.1007/s00424-018-2190-4
Ruiz A, Gautschi I, Schild L, Bonny O. Human mutations in SLC2A9 (Glut9) affect transport capacity for urate. Front Physiol. 2018;9:476.
pubmed: 29967582
pmcid: 6016318
doi: 10.3389/fphys.2018.00476
Kaufmann P, Torok M, Hanni A, Roberts P, Gasser R, Krahenbuhl S, et al. Mechanisms of benzarone and benzbromarone-induced hepatic toxicity. Hepatology. 2005;41:925–35.
pubmed: 15799034
doi: 10.1002/hep.20634
Reinders MK, van Roon EN, Jansen TL, Delsing J, Griep EN, Hoekstra M, et al. Efficacy and tolerability of urate-lowering drugs in gout: a randomised controlled trial of benzbromarone versus probenecid after failure of allopurinol. Ann Rheum Dis. 2009;68:51–6.
pubmed: 18250112
doi: 10.1136/ard.2007.083071
Fleischmann R, Kerr B, Yeh LT, Suster M, Shen Z, Polvent E, et al. Pharmacodynamic, pharmacokinetic and tolerability evaluation of concomitant administration of lesinurad and febuxostat in gout patients with hyperuricaemia. Rheumatol (Oxf). 2014;53:2167–74.
doi: 10.1093/rheumatology/ket487
Hall J, Gillen M, Yang X, Shen Z. Pharmacokinetics, pharmacodynamics, and tolerability of concomitant administration of verinurad and febuxostat in healthy male volunteers. Clin Pharmacol Drug Dev. 2019;8:179–87.
pubmed: 29688628
doi: 10.1002/cpdd.463
Fleischmann R, Winkle P, Hall J, Valdez S, Liu S, Yan X, et al. Pharmacodynamic and pharmacokinetic effects and safety of verinurad in combination with febuxostat in adults with gout: a phase IIa, open-label study. RMD Open. 2018;4:e647.
doi: 10.1136/rmdopen-2017-000584
Rizwan AN, Burckhardt G. Organic anion transporters of the SLC22 family: biopharmaceutical, physiological, and pathological roles. Pharmacol Res. 2007;24:450–70.
doi: 10.1007/s11095-006-9181-4
Yan N. Structural biology of the major facilitator superfamily transporters. Annu Rev Biophys. 2015;44:257–83.
pubmed: 26098515
doi: 10.1146/annurev-biophys-060414-033901
Li DC, Nichols CG, Sala-Rabanal M. Role of a hydrophobic pocket in polyamine interactions with the polyspecific organic cation transporter OCT3. J Biol Chem. 2015;290:27633–43.
pubmed: 26405039
pmcid: 4646014
doi: 10.1074/jbc.M115.668913
Lu J, Dalbeth N, Yin H, Li C, Merriman TR, Wei WH, et al. Mouse models for human hyperuricaemia: a critical review. Nat Rev Rheumatol. 2019;15:413–26.
pubmed: 31118497
doi: 10.1038/s41584-019-0222-x
Alghamdi YS, Soliman MM, Nassan MA. Impact of Lesinurad and allopurinol on experimental hyperuricemia in mice: biochemical, molecular and immunohistochemical study. BMC Pharmacol Toxicol. 2020;21:10.
pubmed: 32041665
pmcid: 7011467
doi: 10.1186/s40360-020-0386-7
Tan Y, Wang L, Gao J, Ma J, Yu H, Zhang Y, et al. Multiomics integrative analysis for discovering the potential mechanism of dioscin against hyperuricemia mice. J Proteome Res. 2020;20:645–60.
pubmed: 33107303
doi: 10.1021/acs.jproteome.0c00584
Chen M, Lu X, Lu C, Shen N, Jiang Y, Chen M, et al. Soluble uric acid increases PDZK1 and ABCG2 expression in human intestinal cell lines via the TLR4-NLRP3 inflammasome and PI3K/Akt signaling pathway. Arthritis Res Ther. 2018;20:20.
pubmed: 29415757
pmcid: 5803867
doi: 10.1186/s13075-018-1512-4
Anzai N, Miyazaki H, Noshiro R, Khamdang S, Chairoungdua A, Shin H, et al. The multivalent PDZ domain-containing protein PDZK1 regulates transport activity of renal urate-anion exchanger URAT1 via its C terminus. J Biol Chem. 2004;279:45942–50.
pubmed: 15304510
doi: 10.1074/jbc.M406724200
Srivastava S, Nakagawa K, He X, Kimura T, Fukutomi T, Miyauchi S, et al. Identification of the multivalent PDZ protein PDZK1 as a binding partner of sodium-coupled monocarboxylate transporter SMCT1 (SLC5A8) and SMCT2 (SLC5A12). J Physiol Sci. 2019;69:399–408.
pubmed: 30604288
doi: 10.1007/s12576-018-00658-1
Mandal AK, Mount DB. The molecular physiology of uric acid homeostasis. Annu Rev Physiol. 2015;77:323–45.
pubmed: 25422986
doi: 10.1146/annurev-physiol-021113-170343
Yano H, Tamura Y, Kobayashi K, Tanemoto M, Uchida S. Uric acid transporter ABCG2 is increased in the intestine of the 5/6 nephrectomy rat model of chronic kidney disease. Clin Exp Nephrol. 2014;18:50–5.
pubmed: 23584883
doi: 10.1007/s10157-013-0806-8
Sekine T, Endou H. The mechanisms of urate transport in the kidney and the intestine. Nihon Rinsho. 1996;54:3237–42.
pubmed: 8976098
Koepsell H. The SLC22 family with transporters of organic cations, anions and zwitterions. Mol Asp Med. 2013;34:413–35.
doi: 10.1016/j.mam.2012.10.010
Xu X, Li C, Zhou P, Jiang T. Uric acid transporters hiding in the intestine. Pharm Biol. 2016;54:3151–5.
pubmed: 27563755
doi: 10.1080/13880209.2016.1195847
Hoque KM, Dixon EE, Lewis RM, Allan J, Gamble GD, Phipps-Green AJ, et al. The ABCG2 Q141K hyperuricemia and gout associated variant illuminates the physiology of human urate excretion. Nat Commun. 2020;11:2767.
pubmed: 32488095
pmcid: 7265540
doi: 10.1038/s41467-020-16525-w
DeBosch BJ, Kluth O, Fujiwara H, Schurmann A, Moley K. Early-onset metabolic syndrome in mice lacking the intestinal uric acid transporter SLC2A9. Nat Commun. 2014;5:4642.
pubmed: 25100214
doi: 10.1038/ncomms5642