| Literature DB >> 28771350 |
Ken Yamada1,2, Julian Levell1, Taeyong Yoon1, Darcy Kohls1, David Yowe1, Dean F Rigel3, Hidetomo Imase1, Jun Yuan1, Kayo Yasoshima1,2, Keith DiPetrillo3, Lauren Monovich1, Lingfei Xu3, Meicheng Zhu1, Mitsunori Kato1,2, Monish Jain1, Neeraja Idamakanti1, Paul Taslimi1, Toshio Kawanami1,2, Upendra A Argikar1, Vidya Kunjathoor1, Xiaoling Xie1, Yukiko I Yagi2, Yuki Iwaki1, Zachary Robinson1, Hyi-Man Park1,2.
Abstract
The observed structure-activity relationship of three distinct ATP noncompetitive With-No-Lysine (WNK) kinase inhibitor series, together with a crystal structure of a previously disclosed allosteric inhibitor bound to WNK1, led to an overlay hypothesis defining core and side-chain relationships across the different series. This in turn enabled an efficient optimization through scaffold morphing, resulting in compounds with a good balance of selectivity, cellular potency, and pharmacokinetic profile, which were suitable for in vivo proof-of-concept studies. When dosed orally, the optimized compound reduced blood pressure in mice overexpressing human WNK1, and induced diuresis, natriuresis and kaliuresis in spontaneously hypertensive rats (SHR), confirming that this mechanism of inhibition of WNK kinase activity is effective at regulating cardiovascular homeostasis.Entities:
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Year: 2017 PMID： 28771350 DOI： 10.1021/acs.jmedchem.7b00708
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446