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Title: Small-molecule WNK inhibition regulates cardiovascular and renal function

Abstract

The With-No-Lysine (K) (WNK) kinases play a critical role in blood pressure regulation and body fluid and electrolyte homeostasis. Herein, we introduce the first orally bioavailable pan-WNK-kinase inhibitor, WNK463, that exploits unique structural features of the WNK kinases for both affinity and kinase selectivity. In rodent models of hypertension, WNK463 affects blood pressure and body fluid and electro-lyte homeostasis, consistent with WNK-kinase-associated physiology and pathophysiology.


Citation Formats

Yamada, Ken, Park, Hyi-Man, Rigel, Dean F., DiPetrillo, Keith, Whalen, Erin J., Anisowicz, Anthony, Beil, Michael, Berstler, James, Brocklehurst, Cara Emily, Burdick, Debra A., Caplan, Shari L., Capparelli, Michael P., Chen, Guanjing, Chen, Wei, Dale, Bethany, Deng, Lin, Fu, Fumin, Hamamatsu, Norio, Harasaki, Kouki, Herr, Tracey, Hoffmann, Peter, Hu, Qi-Ying, Huang, Waan-Jeng, Idamakanti, Neeraja, Imase, Hidetomo, Iwaki, Yuki, Jain, Monish, Jeyaseelan, Jey, Kato, Mitsunori, Kaushik, Virendar K., Kohls, Darcy, Kunjathoor, Vidya, LaSala, Daniel, Lee, Jongchan, Liu, Jing, Luo, Yang, Ma, Fupeng, Mo, Ruowei, Mowbray, Sarah, Mogi, Muneto, Ossola, Flavio, Pandey, Pramod, Patel, Sejal J., Raghavan, Swetha, Salem, Bahaa, Shanado, Yuka H., Trakshel, Gary M., Turner, Gordon, Wakai, Hiromichi, Wang, Chunhua, Weldon, Stephen, Wielicki, Jennifer B., Xie, Xiaoling, Xu, Lingfei, Yagi, Yukiko I., Yasoshima, Kayo, Yin, Jianning, Yowe, David, Zhang, Ji-Hu, Zheng, Gang, and Monovich, Lauren. Small-molecule WNK inhibition regulates cardiovascular and renal function. United States: N. p., 2016. Web. doi:10.1038/nchembio.2168.
Yamada, Ken, Park, Hyi-Man, Rigel, Dean F., DiPetrillo, Keith, Whalen, Erin J., Anisowicz, Anthony, Beil, Michael, Berstler, James, Brocklehurst, Cara Emily, Burdick, Debra A., Caplan, Shari L., Capparelli, Michael P., Chen, Guanjing, Chen, Wei, Dale, Bethany, Deng, Lin, Fu, Fumin, Hamamatsu, Norio, Harasaki, Kouki, Herr, Tracey, Hoffmann, Peter, Hu, Qi-Ying, Huang, Waan-Jeng, Idamakanti, Neeraja, Imase, Hidetomo, Iwaki, Yuki, Jain, Monish, Jeyaseelan, Jey, Kato, Mitsunori, Kaushik, Virendar K., Kohls, Darcy, Kunjathoor, Vidya, LaSala, Daniel, Lee, Jongchan, Liu, Jing, Luo, Yang, Ma, Fupeng, Mo, Ruowei, Mowbray, Sarah, Mogi, Muneto, Ossola, Flavio, Pandey, Pramod, Patel, Sejal J., Raghavan, Swetha, Salem, Bahaa, Shanado, Yuka H., Trakshel, Gary M., Turner, Gordon, Wakai, Hiromichi, Wang, Chunhua, Weldon, Stephen, Wielicki, Jennifer B., Xie, Xiaoling, Xu, Lingfei, Yagi, Yukiko I., Yasoshima, Kayo, Yin, Jianning, Yowe, David, Zhang, Ji-Hu, Zheng, Gang, & Monovich, Lauren. Small-molecule WNK inhibition regulates cardiovascular and renal function. United States. doi:10.1038/nchembio.2168.
Yamada, Ken, Park, Hyi-Man, Rigel, Dean F., DiPetrillo, Keith, Whalen, Erin J., Anisowicz, Anthony, Beil, Michael, Berstler, James, Brocklehurst, Cara Emily, Burdick, Debra A., Caplan, Shari L., Capparelli, Michael P., Chen, Guanjing, Chen, Wei, Dale, Bethany, Deng, Lin, Fu, Fumin, Hamamatsu, Norio, Harasaki, Kouki, Herr, Tracey, Hoffmann, Peter, Hu, Qi-Ying, Huang, Waan-Jeng, Idamakanti, Neeraja, Imase, Hidetomo, Iwaki, Yuki, Jain, Monish, Jeyaseelan, Jey, Kato, Mitsunori, Kaushik, Virendar K., Kohls, Darcy, Kunjathoor, Vidya, LaSala, Daniel, Lee, Jongchan, Liu, Jing, Luo, Yang, Ma, Fupeng, Mo, Ruowei, Mowbray, Sarah, Mogi, Muneto, Ossola, Flavio, Pandey, Pramod, Patel, Sejal J., Raghavan, Swetha, Salem, Bahaa, Shanado, Yuka H., Trakshel, Gary M., Turner, Gordon, Wakai, Hiromichi, Wang, Chunhua, Weldon, Stephen, Wielicki, Jennifer B., Xie, Xiaoling, Xu, Lingfei, Yagi, Yukiko I., Yasoshima, Kayo, Yin, Jianning, Yowe, David, Zhang, Ji-Hu, Zheng, Gang, and Monovich, Lauren. 2016. "Small-molecule WNK inhibition regulates cardiovascular and renal function". United States. doi:10.1038/nchembio.2168.
@article{osti_1404999,
title = {Small-molecule WNK inhibition regulates cardiovascular and renal function},
author = {Yamada, Ken and Park, Hyi-Man and Rigel, Dean F. and DiPetrillo, Keith and Whalen, Erin J. and Anisowicz, Anthony and Beil, Michael and Berstler, James and Brocklehurst, Cara Emily and Burdick, Debra A. and Caplan, Shari L. and Capparelli, Michael P. and Chen, Guanjing and Chen, Wei and Dale, Bethany and Deng, Lin and Fu, Fumin and Hamamatsu, Norio and Harasaki, Kouki and Herr, Tracey and Hoffmann, Peter and Hu, Qi-Ying and Huang, Waan-Jeng and Idamakanti, Neeraja and Imase, Hidetomo and Iwaki, Yuki and Jain, Monish and Jeyaseelan, Jey and Kato, Mitsunori and Kaushik, Virendar K. and Kohls, Darcy and Kunjathoor, Vidya and LaSala, Daniel and Lee, Jongchan and Liu, Jing and Luo, Yang and Ma, Fupeng and Mo, Ruowei and Mowbray, Sarah and Mogi, Muneto and Ossola, Flavio and Pandey, Pramod and Patel, Sejal J. and Raghavan, Swetha and Salem, Bahaa and Shanado, Yuka H. and Trakshel, Gary M. and Turner, Gordon and Wakai, Hiromichi and Wang, Chunhua and Weldon, Stephen and Wielicki, Jennifer B. and Xie, Xiaoling and Xu, Lingfei and Yagi, Yukiko I. and Yasoshima, Kayo and Yin, Jianning and Yowe, David and Zhang, Ji-Hu and Zheng, Gang and Monovich, Lauren},
abstractNote = {The With-No-Lysine (K) (WNK) kinases play a critical role in blood pressure regulation and body fluid and electrolyte homeostasis. Herein, we introduce the first orally bioavailable pan-WNK-kinase inhibitor, WNK463, that exploits unique structural features of the WNK kinases for both affinity and kinase selectivity. In rodent models of hypertension, WNK463 affects blood pressure and body fluid and electro-lyte homeostasis, consistent with WNK-kinase-associated physiology and pathophysiology.},
doi = {10.1038/nchembio.2168},
journal = {Nature Chemical Biology},
number = 11,
volume = 12,
place = {United States},
year = 2016,
month = 9
}
  • The effects of captopril on effective renal plasma flow and glomerular filtration rate were studied using a noninvasive radioisotopic method on individual kidneys in eight patients with renovascular hypertension and 12 patients with essential hypertension with various renin levels. Four patients with renovascular hypertension had unilateral while three had bilateral renal artery stenosis. The effective renal plasma flow and glomerular filtration rate were determined by using /sup 131/I-iodohippurate sodium and /sup 99m/Tc-diethylenetriamine pentaacetic acid, respectively. Glomerular filtration rate and effective renal plasma flow were significantly reduced in the stenotic kidneys of patients with renovascular hypertension compared with values in nonstenoticmore » kidneys (p less than 0.01). Treatment with captopril, 37.5 to 75 mg/day for 1 to 48 weeks, further reduced the glomerular filtration rate only in stenotic kidneys, and effective renal plasma flow increased in both kidney types. In two of the three renal hypertensive patients with bilateral renal artery stenosis, captopril produced a reversible azotemia that was unrelated to the fall in blood pressure, as evidenced by the lack of azotemia seen after a moderate blood pressure reduction induced by other antihypertensive medications. These results indicate that endogenous angiotensin II is essential in maintaining the glomerular filtration rate in stenotic kidneys and suggest that a reduction in glomerular filtration rate during captopril administration could indicate the presence of renal artery stenosis.« less
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