Nanomolar potency and metabolically stable inhibitors of kidney urea transporter UT-B

Journal of Medicinal Chemistry

Volumn 55, Issue 12, 2012, Pages 5942-5950

  Anderson, Marc O ^a   Zhang, Jicheng ^a   Liu, Yan ^a   Yao, Chenjuan ^b   Phuan, Puay Wah ^b   Verkman, A S ^b  

^a SAN FRANCISCO STATE UNIVERSITY   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

3 (4 BROMOBENZENESULFONYL) 4H THIENO[2,3 E][1,2,3]TRIAZOLO[1,5 A]PYRIMIDIN 5 ONE; 3 (4 DIFLUOROETHYLBENZENESULFONYL) 4H THIENO[2,3 E][1,2,3]TRIAZOLO[1,5 A]PYRIMIDIN 5 ONE; 3 (4 FLUOROBENZENESULFONYL) 4H THIENO[2,3 E][1,2,3]TRIAZOLO[1,5 A]PYRIMIDIN 5 ONE; 3 (4 ISOPROPYLBENZENESULFONYL) 4H THIENO[2,3 E][1,2,3]TRIAZOLO[1,5 A]PYRIMIDIN 5 ONE; 3 (4 METHOXYBENZENESULFONYL) 4H THIENO[2,3 E][1,2,3]TRIAZOLO[1,5 A]PYRIMIDIN 5 ONE; 3 (4 TRIFLUOROMETHOXYBENZENESULFONYL) 4H THIENO[2,3 E][1,2,3]TRIAZOLO[1,5 A]PYRIMIDIN 5 ONE; 3 (4 TRIFLUOROMETHYLBENZENESULFONYL) 4H THIENO[2,3 E][1,2,3]TRIAZOLO[1,5 A]PYRIMIDIN 5 ONE; 3 (THIOPHENE 2 SULFONYL) 4H THIENO[2,3 E][1,2,3]TRIAZOLO[1,5 A]PYRIMIDIN 5 ONE; [3 (4 BROMOBENZENESULFONYL)THIENO[2,3 E][1,2,3]TRIAZOLO[1,5 A]PYRIMIDIN 5 YL]THIOPHEN 2 YLMETHYLAMINE; [3 (4 FLUOROBENZENESULFONYL)THIENO[2,3 E][1,2,3]TRIAZOLO[1,5 A]PYRIMIDIN 5 YL]THIOPHEN 2 YLMETHYLAMINE; [3 (4 ISOPROPYLBENZENESULFONYL)THIENO[2,3 E][1,2,3]TRIAZOLO[1,5 A]PYRIMIDIN 5 YL] (4 METHOXYBENZYL)AMINE; [3 (4 ISOPROPYLBENZENESULFONYL)THIENO[2,3 E][1,2,3]TRIAZOLO[1,5 A]PYRIMIDIN 5 YL]THIOPHEN 2 YLMETHYLAMINE; [3 (4 METHOXYBENZENESULFONYL)THIENO[2,3 E][1,2,3]TRIAZOLO[1,5 A]PYRIMIDIN 5 YL]THIOPHEN 2 YLMETHYLAMINE; [3 (THIOPHENE 2 SULFONYL)THIENO[2,3 E][1,2,3]TRIAZOLO[1,5 A]PYRIMIDIN 5 YL]THIOPHEN 2 YLMETHYLAMINE; [3 [4 (1,1 DIFLUOROETHYL)BENZENESULFONYL]THIENO[2,3 E][1,2,3]TRIAZOLO[1,5 A]PYRIMIDIN 5 YL]THIOPHEN 2 YLMETHYLAMINE; [4 (1,1 DIFLUOROETHYL)BENZENESULFONYL]ACETONITRILE; [4 (1,1 DIFLUOROETHYL)PHENYLSULFONYL]ACETIC ACID METHYLESTER; FURAN 2 YLMETHYL [3 (4 ISOPROPYLBENZENESULFONYL)THIENO[2,3 E][1,2,3]TRIAZOLO[1,5 A]PYRIMIDIN 5 YL]AMINE; ISOBUTYL 3 AZIDOTHIOPHENE 2 CARBOXYLIC ACID; PROTEIN INHIBITOR; PYRIMIDINE DERIVATIVE; THIOPHEN 2 YLMETHYL [3 (4 TRIFLUOROMETHOXYBENZENESULFONYL)THIENO[2,3 E][1,2,3]TRIAZOLO[1,5 A]PYRIMIDIN 5 YL]AMINE; THIOPHEN 2 YLMETHYL [3 (4 TRIFLUOROMETHYLBENZENESULFONYL)THIENO[2,3 E][1,2,3]TRIAZOLO[1,5 A]PYRIMIDIN 5 YL]AMINE; TRIAZOLOTHIENOPYRIMIDINE DERIVATIVE; UNCLASSIFIED DRUG; UREA; UREA TRANSPORTER B INHIBITOR;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; DRUG ACCUMULATION; DRUG POTENCY; DRUG STABILITY; DRUG SYNTHESIS; DRUG URINE LEVEL; EDEMA; HEART FAILURE; HUMAN; HUMAN CELL; IC 50; KIDNEY; KIDNEY CONCENTRATING CAPACITY; LIVER FAILURE; MOUSE; NONHUMAN; STRUCTURE ACTIVITY RELATION; TRANSPORT KINETICS; UREA CYCLE;

ANIMALS; DRUG DESIGN; DRUG STABILITY; INHIBITORY CONCENTRATION 50; KIDNEY; MEMBRANE TRANSPORT PROTEINS; MICE; PYRIMIDINES; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84863095475     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm300491y     Document Type: Article

References (28)

1. Yao et al. J. Am. Soc. Nephrol., in press
2. Bankir, L.; Trinh-Trang-Tan, M. M. Urea and the Kidney. In The Kidney. 6 th ed.; Brenner, B. M., Ed.; WB Saunders: Philadelphia, PA, 2000; pp 637-679.
3. Sands, J. M.; Layton, H. E. The physiology of urinary concentration: an update Semin. Nephrol. 2009, 29, 178-195
4. Tsukaguchi, H.; Shayakul, C.; Berger, U. V.; Tokui, T.; Brown, D.; Hediger, M. A. Cloning and characterization of the urea transporter UT3: localization in rat kidney and testis J. Clin. Invest. 1997, 99, 1506-1515
5. Sands, J. M. Renal urea transporters Curr. Opin. Nephrol. Hypertens. 2004, 13, 525-532
6. Stewart, G. The emerging physiological roles of the SLC14A family of urea transporters Br. J. Pharmacol. 2011, 164, 1476-5381
7. Yang, B; Verkman, A. S. Analysis of double knockout mice lacking aquaporin-1 and urea transporter UT-B. Evidence for UT-B-facilitated water transport in erythrocytes J. Biol. Chem. 2002, 277, 36782-36786
8. Bankir, L.; Chen, K.; Yang, B. Lack of UT-B in vasa recta and red blood cells prevents urea-induced improvement of urinary concentrating ability Am. J. Physiol.: Renal Physiol. 2004, 286, F144-F151
9. Fenton, R. A.; Chou, C. L.; Stewart, G. S.; Smith, C. P.; Knepper, M. A. Urinary concentrating defect in mice with selective deletion of phloretin-sensitive urea transporters in the renal collecting duct Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 7469-7474
10. Fenton, R. A.; Flynn, A.; Shodeinde, A.; Smith, C. P.; Schnermann, J.; Knepper, M. A. Renal phenotype of UT-A urea transporter knockout mice J. Am. Soc. Nephrol. 2005, 16, 1583-1592
11. Fenton, R. A. Urea transporters and renal function: lessons from knockout mice Curr. Opin. Nephrol. Hypertens. 2008, 17, 513-518
12. Uchida, S.; Sohara, E.; Rai, T.; Ikawa, M.; Okabe, M.; Sasaki, S. Impaired urea accumulation in the inner medulla of mice lacking the urea transporter UT-A2 Mol. Cell. Biol. 2005, 25, 7357-7363
13. Martial, S.; Neau, P.; Degeilh, F.; Lamotte, H.; Rousseau, B.; Ripoche, P. Urea derivatives as tools for studying the urea-facilitated transport system Pfluegers Arch. 1993, 423, 51-58
14. Levin, M. H.; de la Fuente, R.; Verkman, A. S. Urearetics: a small molecule screen yields nanomolar potency inhibitors of urea transporter UT-B FASEB J. 2007, 21, 551-563
15. Yao, C.; Anderson, M. O.; Zhang, J.; Yang, B.; Phuan, P.; Verkman, A. S. Triazolothienopyrimidine inhibitors of urea transporter UT-B reduce urine concentration. J. Am. Soc. Nephrol. [Online early access]. DOI: 10.1681/ASN.2011070751. Published Online: Apr 5, 2012.
16. Khojasteh-Bakht, S. C.; Rossulek, M. I.; Fouda, H. G.; Prakash, C. Identification of the human cytochrome P450s responsible for the in vitro metabolism of a leukotriene B4 receptor antagonist, CP-195,543 Xenobiotica 2003, 33, 1201-1210
17. Baldwin, S. J.; Clarke, S. E.; Chenery, R. J. Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of rosiglitazone Br. J. Clin. Pharmacol. 1999, 48, 424-432
18. Ivachtchenko, A. V.; Golovina, E. S.; Kadieva, M. G.; Koryakova, A. G.; Kovalenko, S. M.; Mitkin, O. D.; Okun, I. M.; Ravnyeyko, I. M.; Tkachenko, S. E.; Zaremba, O. V. Synthesis and biological study of 3-(phenylsulfonyl)thieno[2, 3- e ][1,2,3]triazolo[1,5- a ]pyrimidines as potent and selective serotonin 5-HT6 receptor antagonists Bioorg. Med. Chem. 2010, 18, 5282-5290
19. Lindgren, B. O.; Nilsson, T.; Husebye, S.; Mikalsen, Ø.; Leander, K.; Swahn, C. G. Preparation of carboxylic acids from aldehydes (including hydroxylated benzaldehydes) by oxidation with chlorite Acta Chem. Scand. 1973, 27, 888
20. Wan, Z. K.; Wacharasindhu, S.; Binnun, E.; Mansour, T. An efficent direct amination of cyclic amides and cyclic ureas Org. Lett. 2006, 8, 2425-2428
21. NAR reactions in heterocyclic amides and ureas J. Org. Chem. 2007, 72, 10194-10210
22. Sands, J. M.; Gargus, J. J.; Frohlich, O.; Gunn, R. B.; Kokko, J. P. Urinary concentrating ability in patients with Jk(a-b-) blood type who lack carrier-mediated urea transport J. Am. Soc. Nephrol. 1992, 2, 1689-1696
23. Lucien, N.; Sidoux-Walter, F.; Olives, B.; Moulds, J.; Le Pennec, P. Y.; Cartron, J. P.; Bailly, P. Characterization of the gene encoding the human Kidd blood group/urea transporter protein. Evidence for splice site mutations in Jknull individuals J. Biol. Chem. 1998, 273, 12973-12980
24. Zhang, W.; Edwards, A. Theoretical effects of UTB urea transporters in the renal medullary microcirculation Am. J. Physiol.: Renal Physiol. 2003, 285, F731-F747
25. Fenton, R. A. Essential role of vasopressin-regulated urea transport processes in the mammalian kidney Pfluegers Arch. 2009, 458, 169-177
26. Smith, C. P. Mammalian urea transporters Exp. Physiol. 2009, 94, 180-185
27. Guo, L.; Zhao, D.; Song, Y.; Meng, Y.; Zhao, H.; Zhao, X.; Yang, B. Reduced urea flux across the blood-testis barrier and early maturation in the male reproductive system in UT-B-null mice Am. J. Physiol.: Cell Physiol. 2007, 293, C305-C312
28. Li, X.; Ran, J.; Zhou, H.; Lei, T.; Zhou, L.; Han, J.; Yang, B. Mice lacking urea transporter UT-B display depression-like behavior J. Mol. Neurosci. 2012, 46, 362-372